Indazole vitronectin receptor antagonist pharmaceuticals

ABSTRACT

The present invention d ribs novel compounds of the formula: 
     
       
         (Q) d —L n —C h , 
       
     
     useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient. The present invention also provides novel compounds useful for monitoring therapeutic angiogenesis treatment and destruction of new angiogenic vasculature. The pharmaceuticals are comprised of a targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety. The imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.

This application is based on U.S. patent application No. 60/080,150, filed Mar. 31, 1998 and U.S. patent application Nos. 60/112,715, 60/112,829, 60/112,732, 60/112,831 filed Dec. 18, 1998, all of which are now abandoned.

FIELD OF THE INVENTION

The present invention provides novel pharmaceuticals useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient. The pharmaceuticals are comprised of a targeting moiety that binds to the vitronectin receptor that is expressed in tumor vasculature, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety. The therapeutically effective radioisotope emits a gamma ray or alpha particle sufficient to be cytotoxic. The imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.

BACKGROUND OF THE INVENTION

Cancer is a major public health concern in the United States and around the world. It is estimated that over 1 million new cases of invasive cancer will be diagnosed in the United States in 1998. The most prevalent forms of the disease are solid tumors of the lung, breast, prostate, colon and rectum. Cancer is typically diagnosed by a combination of in vitro tests and imaging procedures. The imaging procedures include X-ray computed tomography, magnetic resonance imaging, ultrasound imaging and radionuclide scintigraphy. Frequently, a contrast agent is administered to the patient to enhance the image obtained by X-ray CT, MRI and ultrasound, and the administration of a radiopharmaceutical that localizes in tumors is required for radionuclide scintigraphy.

Treatment of cancer typically involves the use of external beam radiation therapy and chemotherapy, either alone or in combination, depending on the type and extent of the disease. A number of chemotherapeutic agents are available, but generally they all suffer from a lack of specificity for tumors versus normal tissues, resulting in considerable side-effects. The effectiveness of these treatment modalities is also limited, as evidenced by the high mortality rates for a number of cancer types, especially the more prevalent solid tumor diseases. More effective and specific treatment means continue to be needed.

Despite the variety of imaging procedures available for the diagnosis of cancer, there remains a need for improved methods. In particular, methods that can better differentiate between cancer and other pathologic conditions or benign physiologic abnormalities are needed. One means of achieving this desired improvement would be to administer to the patient a metallopharmaceutical that localizes specifically in the tumor by binding to a receptor expressed only in tumors or expressed to a significantly greater extent in tumors than in other tissue. The location of the metallopharmaceutical could then be detected externally either by its imageable emission in the case of certain radiopharmaceuticals or by its effect on the relaxation rate of water in the immediate vicinity in the case of magnetic resonance imaging contrast agents.

This tumor specific metallopharmaceutical approach can also be used for the treatment of cancer when the metallopharmaceutical is comprised of a particle emitting radioisotope. The radioactive decay of the isotope at the site of the tumor results in sufficient ionizing radiation to be toxic to the tumor cells. The specificity of this approach for tumors minimizes the amount of normal tissue that is exposed to the cytotoxic agent and thus may provide more effective treatment with fewer side-effects.

Previous efforts to achieve these desired improvements in cancer imaging and treatment have centered on the use of radionuclide labeled monoclonal antibodies, antibody fragments and other proteins or polypeptides that bind to tumor cell surface receptors. The specificity of these radiopharmaceuticals is frequently very high, but they suffer from several disadvantages. First, because of their high molecular weight, they are generally cleared from the blood stream very slowly, resulting in a prolonged blood background in the images. Also, due to their molecular weight they do not extravasate readily at the site of the tumor and then only slowly diffuse through the extravascular space to the tumor cell surface. This results in a very limited amount of the radiopharmaceutical reaching the receptors and thus very low signal intensity in imaging and insufficient cytotoxic effect for treatment.

Alternative approaches to cancer imaging and therapy have involved the use of small molecules, such as peptides, that bind to tumor cell surface receptors. An In-111 labeled somatostatin receptor binding peptide, In-111-DTPA-D-Phe¹-octeotide, is in clinical use in many countries for imaging tumors that express the somatostatin receptor (Baker, et al. Life Sci., 1991, 49, 1583-91 and Krenning, et al., Eur. J. Nucl. Med., 1993, 20, 716-31). Higher doses of this radiopharmaceutical have been investigated for potential treatment of these types of cancer (Krenning, et al., Digestion, 1996, 57, 57-61). Several groups are investigating the use of Tc-99m labeled ananlogs of In-111-DTPA-D-Phe¹-octeotide for imaging and Re-186 labeled analogs for therapy (Flanagan, et al., U.S. Pat. No. 5,556,939, Lyle, et al., U.S. Pat. No. 5,382,654, and Albert et al., U.S. Pat. No. 5,650,134).

Angiogenesis is the process by which new blood vessels are formed from pre-existing capillaries or post capillary venules; it plays a key role in the pathological development of many solid tumor cancers and their metastases. Tumor released cytokines or angiogenic factors stimulate vascular endothelial cells by interacting with specific cell surface receptors for the factors. The endothelial cells then proliferate and invade into the tumor tissue. The endothelial cells differentiate to form lumens, making new vessel offshoots of pre-existing vessels. The new blood vessels then provide nutrients to the tumor permitting further growth and a route for metastasis.

Angiogenesis is also influenced by cell adhesion molecules (Folkman, J., Nature Medicine, 1995, 1, 27-31). The integrin α_(v)β₃ is a receptor for a wide variety of extracellular matrix proteins with an exposed tripeptide Arg-Gly-Asp moiety and mediates cellular adhesion to its ligands: vitronectin, fibronectin, and fibrinogen, among others. The integrin α_(v)β₃ is minimally expressed on normal blood vessels, but, is significantly upregulated on vascular cells within a variety of human tumors. The role of the α_(v)β₃ receptors is to mediate the interaction of the endothelial cells and the extracellular matrix and facilitate the migration of the cells in the direction of the angiogenic signal, the tumor cell population.

Because of the importance of angiogenesis to tumor growth and metastasis, a number of chemotherapeutic approaches are being developed to interfere with or prevent this process. One of these approaches, involves the use of anti-angiogenic proteins such as angiostatin and endostatin. Angiostatin is a 38 kDa fragment of plasminogen that has been shown in animal models to be a potent inhibitor of endothelial cell proliferation. (O'Reilly et. al. , Cell, 1994, 79, 315-328) Endostatin is a 20 kDa C-terminal fragment of collagen XVIII that has also been shown to be a potent inhibitor. (O'Reilly et. al., Cell, 1997, 88, 277-285) Systemic therapy with endostatin has been shown to result in strong anti-tumor activity in animal models. However, human clinical trials of these two chemotherapeutic agents of biological origin have been hampered by lack of availability.

Another approach to anti-angiogenic therapy is to use targeting moieties that interact with endothelial cell surface receptors expressed in the angiogenic vasculature to which are attached chemotherapeutic agents. Burrows and Thorpe (Proc. Nat. Acad. Sci, USA, 1993, 90, 8996-9000) described the use of an antibody-immunotoxin conjugate to eradicate tumors in a mouse model by destroying the tumor vasculature. The antibody was raised against an endothelial cell class II antigen of the major histocompatibility complex and was then conjugated with the cytotoxic agent, deglycosylated ricin A chain. The same group (Clin. Can. Res., 1995, 1, 1623-1634) investigated the use of antibodies raised against the endothelial cell surface receptor, endoglin, conjugated to deglycosylated ricin A chain. Both of these conjugates exhibited potent anti-tumor activity in mouse models. However, both still suffer drawbacks to routine human use. As with most antibodies or other large, foreign proteins, there is considerable risk of immunologic toxicity which could limit or preclude administration to humans. Also, while the vasculature targeting may improve the local concentration of the attached chemotherapeutic agents, the agents still must be cleaved from the antibody carrier and be transported or diffuse into the cells to be cytotoxic.

Thus, it is desirable to provide anti-angiogenic pharmaceuticals and tumor or new vasculature imaging agents which do not suffer from poor diffusion or transportation, possible immunologic toxicity, limited availability, and/or a lack of specificity.

There is also a growing interest in therapeutic angiogenesis to improve blood flow in regions of the body that have become ischemic or poorly perfused. Several investigators are using growth factors administered locally to cause new vasculature to form either in the limbs or the heart. The growth factors VEGF and bFGF are the most common for this application. Recent publications include: Takeshita, S., et. al., J. Clin. Invest., 1994, 93, 662-670; and Schaper, W. and Schaper, J., Collateral Circulation:Heart, Brain, Kidney, Limbs, Kluwer Academic Publishers, Boston, 1993. The main applications that are under investigation in a number of laboratories are for improving cardiac blood flow and in improving peripheral vessal blood flow in the limbs. For example, Henry, T. et. al. (J. Amer. College Cardiology, 1998, 31, 65A) describe the use of recombinant human VEGF in patients for improving myocardial perfusion by therapeutic angiogenesis. Patients received infusions of rhVEGF and were monitored by nuclear perfusion imaging 30 and 60 days post treatment to determine improvement in myocardial perfusion. About 50% of patients showed improvement by nuclear perfusion imaging whereas 5/7 showed new collatoralization by angiography.

Thus, it is desirable to discover a method of monitoring improved cardiac blood flow which is targeted to new collatoral vessels themselves and not, as in nuclear perfusion imaging, a regional consequence of new collateral vessels.

Another therapeutic application of the radiopharmaceuticals of the present invention that emit cytotoxic radiation (Beta and Alpha particles and Auger electons) is in treating rheumatoid arthritis (RA). In RA, the ingrowth of a highly vascularized pannus is caused by the excessive production of angiogenic factors by the infiltrating macrophages, immune cells, or inflammatory cells. Therefore, the radiopharmaceuticals of the present inventions can be used to destroy the new angiogenic vasculature that results and thus treat the disease.

It is one object of the present invention to provide improved anti-angiogenic pharmaceuticals, comprised of a targeting moiety that binds to the vitronectin receptor that is expressed in tumor neovasculature, an optional linking group, and a radioisotope. The vitronectin receptor binding compounds target the radioisotope to the tumor neovasculature. The beta or alpha-particle emitting radioisotope emits a cytotoxic amount of ionizing radiation which results in cell death. The penetrating ability of radiation obviates the requirement that the cytotoxic agent diffuse or be transported into the cell to be cytotoxic.

It is another object of the present invention to provide tumor imaging agents, comprised of tumor neovasculature vitronectin receptor binding compounds conjugated to an imageable moiety, such as a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.

SUMMARY OF THE INVENTION

It is one object of the present invention to provide anti-angiogenic pharmaceuticals, comprised of a targeting moiety that binds to a receptor that is expressed in tumor neovasculature, an optional linking group, and a radioactive metal ion that emits ionizing radiation such as beta particles, alpha particles and Auger or Coster-Kronig electrons. The receptor binding compounds target the radioisotope to the tumor neovasculature. The beta or alpha-particle emitting radioisotope emits a cytotoxic amount of ionizing radiation which results in cell death. The penetrating ability of radiation obviates the requirement that the cytotoxic agent diffuse or be transported into the cell to be cytotoxic.

It is another object of the present invention to provide pharmaceuticals to treat rheumatoid arthritis. These pharmaceuticals comprise a targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and a radioisotope that emits cytotoxic radiation (i.e., beta particles, alpha particles and Auger or Coster-Kronig electrons). In rheumatoid arthritis, the ingrowth of a highly vascularized pannus is caused by the excessive production of angiogenic factors by the infiltrating macrophages, immune cells, or inflammatory cells. Therefore, the radiopharmaceuticals of the present invention that emit cytotoxic radiation could be used to destroy the new angiogenic vasculature that results and thus treat the disease.

It is another object of the present invention to provide tumor imaging agents, comprised of targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and an imageable moiety, such as a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.

It is another object of the present invention to provide imaging agents for monitoring the progress and results of therapeutic angiogenesis treatment. These agents comprise of targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and an imageable moiety. Imaging agents of the present invention could be administered intravenously periodically after the administration of growth factors and imaging would be performed using standard techniques of the affected areas, heart or limbs, to monitor the progress and results of the therapeutic angiogenesis treatment (i.e., image the formation of new blood vessels).

It is another object of the present invention to provide compounds useful for preparing the pharmaceuticals of the present invention. These compounds are comprised of a peptide or peptidomimetic targeting moiety that binds to a receptor that is upregulated during angiogenesis, Q, an optional linking group, L_(n), and a metal chelator or bonding moiety, C_(h). The compounds may have one or more protecting groups attached to the metal chelator or bonding moiety. The protecting groups provide improved stability to the reagents for long-term storage and are removed either immediately prior to or concurrent with the synthesis of the radiopharmaceuticals. Alternatively, the compounds of the present invention are comprised of a peptide or peptidomimetic targeting moiety that binds to a receptor that is upregulated during angiogenesis, Q, an optional linking group, L_(n), and a surfactant, S_(f).

The pharmaceuticals of the present invention may be used for diagnostic and/or therapeutic purposes. Diagnostic radiopharmaceuticals of the present invention are pharmaceuticals comprised of a diagnostically useful radionuclide (i.e., a radioactive metal ion that has imageable gamma ray or positron emissions). Therapeutic radiopharmaceuticals of the present invention are pharmaceuticals comprised of a therapeutically useful radionuclide, a radioactive metal ion that emits ionizing radiation such as beta particles, alpha particles and Auger or Coster-Kronig electrons.

The pharmaceuticals comprising a gamma ray or positron emitting radioactive metal ion are useful for imaging tumors by gamma scintigraphy or positron emission tomography. The pharmaceuticals comprising a gamma ray or positron emitting radioactive metal ion are also useful for imaging therapeutic angiogenesis by gamma scintigraphy or positron emission tomography. The pharmaceuticals comprising a particle emitting radioactive metal ion are useful for treating cancer by delivering a cytotoxic dose of radiation to the tumors. The pharmaceuticals comprising a particle emitting radioactive metal ion are also useful for treating rheumatoid arthritis by destroying the formation of angiogenic vasculature. The pharmaceuticals comprising a paramagnetic metal ion are useful as magnetic resonance imaging contrast agents. The pharmaceuticals comprising one or more X-ray absorbing or “heavy” atoms of atomic number 20 or greater are useful as X-ray contrast agents. The pharmaceuticals comprising a microbubble of a biocompatible gas, a liquid carrier, and a surfactant microsphere, are useful as ultrasound contrast agents.

DETAILED DESCRIPTION OF THE INVENTION

[1] Thus, in a first embodiment, the present invention provides a novel compound, comprising: a targeting moiety and a chelator, wherein the targeting moiety is bound to the chelator, is a indazole nonpeptide, and binds to a receptor that is upregulated during angiogenesis and the compound has 0-1 linking groups between the targeting moiety and chelator.

[2] In a preferred embodiment, the targeting moiety comprises an indazole and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α_(v)β₃, α_(v)β₅, α₅β₁, α₄β₁, α₁β₁, and α₂β₂ and the linking group is present between the targeting moiety and chelator.

[3] In a more preferred embodiment, the receptor is the integrin α_(v)β₃ and the compound is of the formula:

(Q)_(d)—L_(n)—C_(h) or (Q)_(d)—L_(n)—(C_(h))_(d′)

wherein:

Q is a compound of Formula Ia:

 and pharmaceutically acceptable salt forms thereof, wherein:

X^(1d), X^(2d), X^(3d), and X^(4d) are independently selected from nitrogen or carbon provided that at least two of X^(1d), X^(2d), X^(3d) and X^(4d) are carbon;

R^(1d) is selected from:

A^(d) and B^(d) are independently —CH₂—, —O—, —N(R^(2d))—, or —C(═O)—;

A^(1d) and B^(1d) are independently —CH₂— or —N(R^(3d))—;

D^(d) is —N(R^(2d))—, —O—, —S—, —C(═O)— or —SO₂—;

E^(d)—F^(d) is —C(R^(4d))═C(R^(5d))—, —N═C(R^(4d))—, —C(R^(4d))═N—, or —C(R^(4d))₂C(R^(5d))₂—;

J^(d), K^(d), L^(d) and M^(d) are independently selected from —C(R^(4d))—, —C(R^(5d))— or —N—, provided that at least one of J^(d), K^(d), L^(d) and M^(d) is not —N—;

R^(2d) is selected from: H, C₁-C₆ alkyl, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl; (C₁-C₆ alkyl)aminocarbonyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, heteroaryl(C₁-C₆ alkyl)carbonyl, heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl-, arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl, aryloxycarbonyl, or aryl(C₁-C₆ alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro;

R^(3d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₁-C₆ alkyl)-;

R^(4d) and R^(5d) are independently selected from: H, C₁-C₄ alkoxy, NR^(2d)R^(3d), halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl, or alternatively, when substituents on adjacent atoms, R^(4d) and R^(5d) can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃, or NO₂;

U^(d) is selected from:

—(CH₂)_(n) ^(d)—,

—(CH₂)_(n) ^(d)(CR^(7d)═CR^(8d))(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)(C≡C)(CH₂)_(m) ^(d)—,

—(CH₂)_(t) ^(d)Q(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)O(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)N(R^(6d))(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)C(═O)(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)(C═O)N(R^(6d))(CH₂)_(m) ^(d)—

—(CH₂)_(n) ^(d)N(R^(6d))(C═O)(CH₂)_(m) ^(d)—, or

—(CH₂)_(n) ^(d)S(O)_(p) ^(d)(CH₂)_(m) ^(d)—;

wherein one or more of the methylene groups in U^(d) is optionally substituted with R^(7d);

Q^(d) is selected from 1,2-cycloalkylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 2,4-pyridinylene, or 3,4-pyridazinylene;

R^(6d) is selected from: H, C₁-C₄ alkyl, or benzyl;

R^(7d) and R^(8d) are independently selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₀-C₆ alkyl)-;

R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), N(R^(6d))₂, halogen, NO₂, CN, CF₃, CO₂R^(17d), C(═O)R^(17d), CONR^(17d)R^(20d), —SO₂R^(17d), —SO₂NR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₆ alkenyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₇ cycloalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₄-C₁₁ cycloalkylalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), aryl substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d), or aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d); R^(11d) is selected from H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)R^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d);

W^(d) is selected from: —(C(R^(12d))₂)_(q) ^(d)C(═O)N(R^(13d))—, or —C(═O)—N(R^(13d))—(C(R^(12d))₂)_(q) ^(d)—;

X^(d) is —C(R^(12d))(R^(14d))—C(R^(12d))(R^(15d))—; or alternatively, W^(d) and X^(d) can be taken together to be

R^(12d) is selected from H, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₄-C₁₀ cycloalkylalkyl, (C₁-C₄ alkyl)carbonyl, aryl, or aryl(C₁-C₆ alkyl)-;

R^(13d) is selected from H, C₁-C₆ alkyl, C₃-C₇ cycloalkylmethyl, or aryl (C₁-C₆ alkyl)-;

R^(14d) is selected from: H, C₁-C₆ alkylthio(C₁-C₆ alkyl)-, aryl(C₁-C₁₀ alkylthioalkyl)-, aryl (C₁-C₁₀ alkoxyalkyl)-, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₆ hydroxyalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, heteroaryl (C₁-C₆ alkyl)-, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), or CONR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0-1 R^(16d) or 0-2 R^(11d);

R^(15d) is selected from: H, R^(16d), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ alkylaminoalkyl, C₁-C₁₀ dialkylaminoalkyl, (C₁-C₁₀ alkyl)carbonyl, aryl(C₀-C₆ alkyl)carbonyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl ,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, heteroaryl(C₁-C₆ alkyl)-, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), CONR^(17d)R^(20d), SO₂R^(17d), or SO₂NR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0-2 R^(11d);

Y^(d) is selected from: —COR^(19d), —SO₃H, —PO₃H, tetrazolyl, —CONHNHSO₂CF₃, —CONHSO₂R^(17d), —CONHSO₂NHR^(17d), —NHCOCF₃, —NHCONHSO₂R^(17d), —NHSO₂R^(17d), —OPO₃H₂, —OSO₃H, —PO₃H₂, —SO₃H, —SO₂NHCOR^(17d), —SO₂NHCO₂R^(17d),

R^(16d) is selected from:

—N(R^(20d))—C(═O)—O—R^(17d),

—N(R^(20d))—C(═O)—R^(17d),

—N(R^(20d))—C(═O)—NH—R^(17d),

—N(R^(20d))SO₂—R^(17d), or

—N(R^(20d))SO₂—NR^(20d)R^(17d);

R^(17d) is selected from:

C₁-C₁₀ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁ cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)aryl optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to L_(n), biaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), heteroaryl optionally substituted with a bond to L_(n), aryl optionally substituted with a bond to L_(n), or a bond to L_(n), wherein said aryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, heteroaryl, halo, cyano, amino, CF₃, and NO₂;

R^(18d) is selected from:

H,

—C(═O)—O—R^(17d),

—C(═O)—R^(17d),

—C(═O)—NH—R^(17d),

—SO₂—R^(17d), or

—SO₂—NR^(20d)R^(17d);

R^(19d) is selected from: hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy, aryloxy, aryl(C₁-C₆ alkoxy)-, C₃-C₁₀ alkylcarbonyloxyalkyloxy, C₃-C₁₀ alkoxycarbonyloxyalkyloxy, C₂-C₁₀ alkoxycarbonylalkyloxy, C₅-C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonylalkyloxy, C₇-C₁₁ aryloxycarbonylalkyloxy, C₈-C₁₂ aryloxycarbonyloxyalkyloxy, C₈-C₁₂ arylcarbonyloxyalkyloxy, C₅-C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅-C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀-C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R^(11d))(R^(12d))N—(C₁-C₁₀ alkoxy)-;

R^(20d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₁-C₆ alkyl)-;

R^(21d) is selected from: COOH or (NR^(6d))₂;

m^(d) is 0-4;

n^(d) is 0-4;

t^(d) is 0-4;

p^(d) is 0-2;

q^(d) is 0-2; and

r^(d) is 0-2;

with the following provisos:

(1)_(t) ^(d), n^(d), m^(d) and q^(d) are chosen such that the number of atoms connecting R^(1d) and Y^(d) is in the range of 10-14; and

(2)_(n) ^(d) and m^(d) are chosen such that the value of n^(d) plus m^(d) is greater than one unless U^(d) is —(CH₂)_(t) ^(d)Q^(d) (CH₂)_(m) ^(d)—;

d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

L_(n) is a linking group having the formula:

(CR⁶R⁷)_(g)—(W)_(h)—(CR^(6a)R^(7a))_(g′)—(Z)_(k)—(W)_(h′)—(CR⁸R⁹)_(g″)—(W)_(h″)—(CR^(8a)R^(9a))_(g″′)—(W)_(h″′)—(CR^(8b)R^(9b))_(g″″)—;

W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, SO₂NH, (OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), (CH₂CH₂CH₂O)_(t), and (aa)_(t′);

aa is independently at each occurrence an amino acid;

Z is selected from the group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁰;

R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R^(8b), R⁹, R^(9a) and R^(9b) are independently selected at each occurrence from the group: H, ═O, COOH, SO₃H, PO₃H, C₁-C₅ alkyl substituted with 0-3 R¹⁰, aryl substituted with 0-3 R¹⁰, benzyl substituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to C_(h);

R¹⁰ is independently selected at each occurrence from the group: a bond to C_(h), COOR¹¹, C(═O)NHR¹¹, NHC(═O)R¹¹, OH, NHR¹¹, SO₃H, PO₃H, —OPO₃H₂, —OSO₃H, aryl substituted with 0-3 R¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1 R¹², and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹¹;

R¹¹ is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R¹², aryl substituted with 0-1 R¹², a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycol substituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹², cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1 R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substituted with 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C_(h);

R¹² is a bond to C_(h);

k is selected from 0, 1, and 2;

h is selected from 0, 1, and 2;

h′ is selected from 0, 1, 2, 3, 4, and 5;

h″ is selected from 0, 1, 2, 3, 4, and 5;

h″′ is selected from 0, 1, 2, 3, 4, and 5;

g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g″′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g″″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

C_(h) is a metal bonding unit having a formula selected from the group:

A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at each occurrence from the group: NR¹³, NR¹³R¹⁴, S, SH, S(Pg), O, OH, PR¹³, PR¹³R¹⁴, P(O)R¹⁵R¹⁶, and a bond to L_(n);

E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷;

R¹³ and R¹⁴ are each independently selected from the group: a bond to L_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₁₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³ or R¹⁴ is an electron, then the other is also an electron; alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹);

R¹⁵ and R¹⁶ are each independently selected from the group: a bond to L_(n), —OH, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷;

R¹⁷ is independently selected at each occurrence from the group: a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸, —C(═O)R¹⁸, —C(═O)N(R¹⁸)₂, —CHO, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)OR^(18a), —OR¹⁸, —OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂, —NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —SR¹⁸, —S(═O)R^(18a), —SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, NO₂, —C(═O)NHOR¹⁸, —C(═O)NHNR¹⁸R^(18a), —OCH₂CO₂H, 2-(1-morpholino)ethoxy, C₁-C₅ alkyl, C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylmethyl, C₂-C₆ alkoxyalkyl, aryl substituted with 0-2 R¹⁸, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;

R¹⁸, R^(18a), and R¹⁹ are independently selected at each occurrence from the group: a bond to L_(n), H, C₁-C₆ alkyl, phenyl, benzyl, C₁-C₆ alkoxy, halide, nitro, cyano, and trifluoromethyl;

Pg is a thiol protecting group;

R²⁰ and R²¹ are independently selected from the group: H, C₁-C₁₀ alkyl, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, C₂-C₁₀ 1-alkene substituted with 0-3 R²³, C₂-C₁₀ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3 R²³, unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R²³, and unsaturated C₃₋₁₀ carbocycle substituted with 0-3 R²³; alternatively, R²⁰ and R²¹, taken together with the divalent carbon radical to which they are attached form:

R²² and R²³ are independently selected from the group: H, R²⁴, C₁-C₁₀ alkyl substituted with 0-3 R²⁴, C₂-C₁₀ alkenyl substituted with 0-3 R²⁴, C₂-C₁₀ alkynyl substituted with 0-3 R²⁴, aryl substituted with 0-3 R²⁴, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R²⁴, and C₃₋₁₀ carbocycle substituted with 0-3 R²⁴; alternatively, R²², R²³ taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;

a and b indicate the positions of optional double bonds and n is 0 or 1;

R²⁴ is independently selected at each occurrence from the group: ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, —N(R²⁵)₃+, —CH₂OR²⁵, —OC(═O)R²⁵, —OC(═O)OR^(25a), —OR²⁵, —OC(═O)N(R²⁵)₂, —NR²⁶C(═O)R²⁵, —NR²⁶C(═O)OR^(25a), —NR²⁶C(═O)N(R²⁵)₂, —NR²⁶SO₂N(R²⁵)₂, —NR²⁶SO₂R^(25a), —SO₃H, —SO₂R^(25a), —SR²⁵, —S(═O)R^(25a), —SO₂N(R²⁵)₂, —N(R²⁵)₂, ═NOR²⁵, —C(═O)NHOR²⁵, —OCH₂CO₂H, and 2-(1-morpholino)ethoxy; and,

R²⁵, R^(25a), and R²⁶ are each independently selected at each occurrence from the group: hydrogen and C₁-C₆ alkyl;

and a pharmaceutically acceptable salt thereof.

[4] In an even more preferred embodiment, the present invention provides a compound, wherein:

Q is a compound of Formula Ia:

 and pharmaceutically acceptable salt forms thereof, wherein:

X^(1d), X^(2d), X^(3d), and X^(4d) are independently selected from nitrogen or carbon provided that at least two of X^(1d), X^(2d), X^(3d) and X^(4d) are carbon;

R^(1d) is selected from:

A^(d) and B^(d) are independently —CH₂—, —O—, —N(R^(2d))—, or —C(═O)—;

A^(1d) and B^(1d) are independently —CH₂— or —N(R^(3d))—;

D^(d) is —N(R^(2d))—, —O—, —S—, —C(═O)— or —SO₂—;

E^(d)—F^(d) is —C(R^(4d))═C(R^(5d))—, —N═C(R^(4d))—, —C(R^(4d))═N—, or —C(R^(4d))₂C(R^(5d))₂—;

J^(d), K^(d), L^(d) and M^(d) are independently selected from —C(R^(4d))—, —C(R^(5d))— or —N—, provided that at least one of J^(d), K^(d), L^(d) and M^(d) is not —N—;

R^(2d) is selected from: H, C₁-C₆ alkyl, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, C₁-C₆ alkylaminocarbonyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, heteroaryl(C₁-C₆ alkyl)carbonyl, heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl, aryloxycarbonyl, or aryl(C₁-C₆ alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro;

R^(3d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl (C₁-C₆ alkyl)-, or heteroaryl(C₁-C₆ alkyl)-;

R^(4d) and R^(5d) are independently selected from: H, C₁-C₄ alkoxy, NR^(2d)R^(3d), halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, C₂-C₇ alkylcarbonyl, arylcarbonyl or alternatively, when substituents on adjacent atoms, R^(4d) and R^(5d) can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃, or NO₂;

U^(d) is selected from:

—(CH₂)_(n) ^(d)—,

—(CH₂)_(n) ^(d)(CR^(7d)═CR^(8d))(CH₂)_(m) ^(d)—,

—(CH₂)_(t) ^(d)Q^(d)(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)O(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)N(R^(6d))(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)C(═O)(CH₂)_(m) ^(d)—, or

—(CH₂)_(n) ^(d)S(O)_(p) ^(d)(CH₂)_(m) ^(d)—;

wherein one or more of the methylene groups in U^(d) is optionally substituted with R^(7d);

Q^(d) is selected from 1,2-phenylene, 1,3-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, or 2,4-pyridinylene;

R^(6d) is selected from: H, C₁-C₄ alkyl, or benzyl;

R^(7d) and R^(8d) are independently selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₀-C₆ alkyl)-;

R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), N(R^(6d))₂, halogen, NO₂, CN, CF₃, CO₂R^(17d) C(═O)R^(17d), CONR^(17d)R^(20d), —SO₂R^(17d), —SO₂NR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₆ alkenyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₇ cycloalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₄-C₁₁ cycloalkylalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), aryl substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d), or aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d);

R^(11d) is selected from: H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)Rd^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d);

W^(d) is —C(═O)—N(R^(13d))—(C(R^(12d))₂)_(q) ^(d)—;

x^(d) is —C(R^(12d))(R^(14d))—C(R^(12d))(R^(15d))—; alternatively, W^(d) and X^(d) can be taken together to be

R^(12d) is H or C₁-C₆ alkyl;

R^(13d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkylmethyl, or aryl(C₁-C₆ alkyl)-;

R^(14d) is selected from: H, C₁-C₆ alkylthioalkyl, aryl (C₁-C₁₀ alkylthioalkyl)-, aryl (C₁-C₁₀ alkoxyalkyl)-, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₆ hydroxyalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, heteroaryl(C₁-C₆ alkyl)-, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), or CONR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be substituted independently with 0-1 R^(16d) or 0-2 R^(11d);

R^(15d) is selected from: H, R^(16d), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ alkylaminoalkyl, C₁-C₁₀ dialkylaminoalkyl, C₁-C₁₀ alkylcarbonyl, aryl(C₀-C₆ alkyl)carbonyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl ,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, heteroaryl(C₁-C₆ alkyl)-, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), CONR^(17d)R^(20d), SO₂R^(17d), or SO₂NR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be substituted independently with 0-2 R^(11d);

Y^(d) is selected from:

—COR^(19d), —SO₃H,

R^(16d) is selected from:

—N(R^(20d))—C(═O)—O—R^(17d),

—N(R^(20d))—C(═O)—R^(17d),

—N(R^(20d))—C(═O)—NH—R^(17d),

—N(R^(20d))SO₂—R^(17d), or

—N(R^(20d))SO₂—NR^(20d)R^(17d);

R^(17d) is selected from: C₁-C₁₀ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁ cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)aryl optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to L_(n), biaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), heteroaryl optionally substituted with a bond to L_(n), aryl optionally substituted with a bond to L_(n), or a bond to L_(n), wherein said aryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, heteroaryl, halo,cyano, amino, CF₃, and NO₂;

R^(18d) is selected from:

H,

—C(═O)—O—R^(17d),

—C(═O)—R^(17d),

—C(═O)—NH—R¹⁷,

—SO₂—R^(17d), or

—SO₂—NR^(20d)R^(17d);

R^(19d) is selected from: hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy, C₆-C₁₀ aryloxy, C₇-C₁₁ aralkyloxy, C₃-C₁₀ alkylcarbonyloxyalkyloxy, C₃-C₁₀ alkoxycarbonyloxyalkyloxy, C₂-C₁₀ alkoxycarbonylalkyloxy, C₅-C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonylalkyloxy, C₇-C₁₁ aryloxycarbonylalkyloxy, C₈-C₁₂ aryloxycarbonyloxyalkyloxy, C₈-C₁₂ arylcarbonyloxyalkyloxy, C₅-C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅-C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀-C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R^(11d))(R^(12d))N—(C₁-C₁₀ alkoxy)-;

R^(20d) selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₁-C₆ alkyl)-;

R^(21d) is selected from COOH or (NR^(6d))₂;

m^(d) is 0-4;

n^(d) is 0-4;

p^(d) is 0-2;

q^(d) is 0-2;

t^(d) is 0-4;

r^(d) is 0-2;

d is selected from 1, 2, 3, 4, and 5;

W is independently selected at each occurrence from the group: O, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, (OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), and (CH₂CH₂CH₂O)_(t),

Z is selected from the group: aryl substituted with 0-1 R¹⁰, C₃₋₁₀ cycloalkyl substituted with 0-1 R¹⁰, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R¹⁰;

R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R^(8b), R⁹, R^(9a) and R^(9b) are independently selected at each occurrence from the group: H, ═O, COOH, SO₃H, C₁-C₅ alkyl substituted with 0-1 R¹⁰, aryl substituted with 0-1 R¹⁰, benzyl substituted with 0-1 R¹⁰, and C₁-C₅ alkoxy substituted with 0-1 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to C_(h);

R¹⁰ is independently selected at each occurrence from the group: a bond to C_(h), COOR¹¹, C(═O)NHR¹¹, NHC(═O)R¹¹, OH, NHR¹¹, SO₃H, PO₃H, —OPO₃H₂, —OSO₃H, aryl substituted with 0-3 R¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1 R¹², and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹¹;

R¹¹ is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R¹², aryl substituted with 0-1 R¹², a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycol substituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹², cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1 R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substituted with 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C_(h);

k is 0 or 1;

s is selected from 0, 1, 2, 3, 4, and 5;

s′ is selected from 0, 1, 2, 3, 4, and 5;

s″ is selected from 0, 1, 2, 3, 4, and 5;

t is selected from 0, 1, 2, 3, 4, and 5;

A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at each occurrence from the group: NR¹³, NR¹³R¹⁴, S, SH, S(Pg), OH, and a bond to L_(n);

E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷;

R¹³, and R¹⁴ are each independently selected from the group: a bond to L_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³ or R¹⁴ is an electron, then the other is also an electron; alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹);

R¹⁷ is independently selected at each occurrence from the group: a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸, —C(═O)R¹⁸, —C(═O)N(R¹⁸)₂, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)OR^(18a), —OR¹⁸, —OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂, —NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —S(═O)R^(18a), —SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, —C(═O)NHNR¹⁸R^(18a), —OCH₂CO₂H, and 2-(1-morpholino)ethoxy;

R¹⁸, R^(18a), and R¹⁹ are independently selected at each occurrence from the group: a bond to L_(n), H, and C₁-C₆ alkyl;

R²⁰ and R²¹ are independently selected from the group: H, C₁-C₅ alkyl, —CO₂R²⁵, C₂-C₅ 1-alkene substituted with 0-3 R²³, C₂-C₅ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3 R²³, and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R²³; alternatively, R²⁰ and R²¹, taken together with the divalent carbon radical to which they are attached form:

R²² and R²³ are independently selected from the group: H, and R²⁴; alternatively, R²², R²³ taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;

R²⁴ is independently selected at each occurrence from the group: —CO₂R²⁵, —C(═O)N(R²⁵)₂, —CH₂OR²⁵, —OC(═O)R²⁵, —OR²⁵, —SO₃H, —N(R²⁵)₂, and —OCH₂CO₂H; and,

R²⁵ is independently selected at each occurrence from the group: H and C₁-C₃ alkyl.

[5] In a still more preferred embodiment, the present invention provides a compound, wherein:

Q is a compound of Formula IIa or IIb:

 and pharmaceutically acceptable salt forms thereof wherein:

X^(1d) and X^(3d) are independently selected from nitrogen or carbon;

R^(1d) is selected from:

 wherein the above heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH₂, halogen, NO₂, CN, CF₃, C₁-C₄ alkoxy, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl;

U^(d) is —(CH₂)_(n)—, —(CH₂)_(t) ^(d)Q^(d)(CH₂)_(m) ^(d)— or —C(═O)(CH₂)_(n) ^(d)—1⁻, wherein one of the methylene groups is optionally substituted with R^(7d);

Q^(d) is selected from 1,2-phenylene, 1,3-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, or 2,4-pyridinylene;

R^(6d) is selected from: H, C₁-C₄ alkyl, or benzyl;

R^(7d) is selected from: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl), heteroaryl, or heteroaryl(C₁-C₆ alkyl);

R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), halogen, CO₂R^(17d), CONR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₇ cycloalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₄-C₁₁ cycloalkylalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), or aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d);

R^(11d) is selected from: H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)R^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d);

W^(d) is —C(═O)—N(R^(13d))—;

X^(d) is —CH(R^(14d))—CH(R^(15d))—;

R¹³ ^(d) is H or CH₃;

R^(14d) is selected from: H, C₁-C₁₀ alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, halo, cyano, amino, CF₃, and NO₂;

R^(15d) is H or R^(16d);

Y^(d) is —COR^(19d);

R^(16d) is selected from:

—NH(R^(20d))—C(═O)—O—R^(17d),

—N(R^(20d))—C(═O)—R^(17d),

—N(R^(20d))—C(═O)—NH—R^(17d),

—N(R^(20d))SO₂—R^(17d), or

—N(R^(20d))SO₂—N(R^(20d))R^(17d);

R^(17d) is selected from: C₁-C₁₀ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁ cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)aryl optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to L_(n), biaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), heteroaryl optionally substituted with a bond to L_(n), aryl optionally substituted with a bond to L_(n), or a bond to L_(n), wherein said aryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, heteroaryl, halo,cyano, amino, CF₃, and NO₂;

R^(19d) is selected from:

hydroxy, C₁-C₁₀ alkoxy,

methylcarbonyloxymethoxy-,

ethylcarbonyloxymethoxy-,

t-butylcarbonyloxymethoxy-,

cyclohexylcarbonyloxymethoxy-,

1-(methylcarbonyloxy)ethoxy-,

1-(ethylcarbonyloxy)ethoxy-,

1-(t-butylcarbonyloxy)ethoxy-,

1-(cyclohexylcarbonyloxy)ethoxy-,

i-propyloxycarbonyloxymethoxy-,

t-butyloxycarbonyloxymethoxy-,

1-(1-propyloxycarbonyloxy)ethoxy-,

1-(cyclohexyloxycarbonyloxy)ethoxy-,

1-(t-butyloxycarbonyloxy)ethoxy-,

dimethylaminoethoxy-,

diethylaminoethoxy-,

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-, or

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R^(20d) is H or CH₃;

R^(21d) is selected from COOH or (NR^(6d))₂;

m^(d) is 0 or 1;

n^(d) is 1-4;

t^(d) is 0 or 1;

or Q is a peptide selected from the group:

R¹ is L-valine, D-valine or L-lysine optionally substituted on the ε amino group with a bond to L_(n);

R² is L-phenylalanine, D-phenylalanine, D-1-naphthylalanine, 2-aminothiazole-4-acetic acid or tyrosine, the tyrosine optionally substituted on the hydroxy group with a bond to L_(n);

R³ is D-valine;

R⁴ is D-tyrosine substituted on the hydroxy group with a bond to L_(n);

provided that one of R¹ and R² in each Q is substituted with a bond to L_(n), and further provided that when R² is 2-aminothiazole-4-acetic acid, K is N-methylarginine;

d is 1, 2, 3, 4, or 5;

provided that at least one Q is a compound of Formula IIa or IIb;

C_(h) is

A¹ is selected from the group: OH, and a bond to L_(n);

A², A⁴, and A⁶ are each N;

A³, A⁵, and A⁸ are each OH;

A⁷ is a bond to L_(n) or NH-bond to L_(n);

E is a C₂ alkyl substituted with 0-1 R¹⁷;

R¹⁷ is ═O; alternatively, C_(h) is

A¹ is selected from the group: OH, and a bond to L_(n);

A², A³ and A⁴ are each N;

A⁵, A⁶ and A⁸ are each OH;

A⁷ is a bond to L_(n);

E is a C₂ alkyl substituted with 0-1 R¹⁷;

R¹⁷ is ═O; alternatively, C_(h) is

A¹ is NH₂ or N═C(R²⁰)(R²¹);

E is a bond;

A² is NHR¹³;

R¹³ is a heterocycle substituted with R¹⁷, the heterocycle being selected from pyridine and pyrimidine;

R¹⁷ is selected from a bond to L_(n), C(═O)NHR¹⁸ and C(═O)R¹⁸;

R¹⁸ is a bond to L_(n);

R²⁴ is selected from the group: —CO₂R²⁵, —OR²⁵, —SO₃H, and —N(R²⁵)₂; and,

R²⁵ is independently selected at each occurrence from the group: hydrogen and methyl.

[6] In another even more preferred embodiment, Q is a compound of Formula IIa or IIb:

and pharmaceutically acceptable salt forms thereof wherein:

X^(1d) and X^(3d) are independently selected from nitrogen or carbon, provided that at least one of X^(1d) and X^(3d) is carbon;

R^(1d) is selected from:

 wherein the above heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH₂, halogen, NO₂, CN, CF₃, C₁-C₄ alkoxy, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl;

U^(d) is —(CH₂)_(n)—, —(CH₂)_(t) ^(d)Q^(d)(CH₂)_(m) ^(d)— or —C(═O)(CH₂)_(n) ^(d)—1^(—), wherein one of the methylene groups is optionally substituted with R⁷ ^(d) ;

Q^(d) is selected from 1,2-phenylene, 1,3-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, or 2,4-pyridinylene;

R^(6d) is selected from: H, C₁-C₄ alkyl, or benzyl;

R^(7d) is selected from: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl), heteroaryl, or heteroaryl(C₁-C₆ alkyl);

R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), halogen, CO₂R^(17d), CONR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₇ cycloalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₄-C₁₁ cycloalkylalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), or aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d);

R^(11d) is selected from: H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)R^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d);W is —C(═O)—N(R^(13d))—;

W^(d) is —C(═O)—N(R^(13d))—;

X^(d) is —CH(R^(14d))—CH(R^(15d))—;

R^(13d) is H or CH₃;

R^(14d) is selected from: H, C₁-C₁₀ alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, halo, cyano, amino, CF₃, and NO₂;

R^(15d) is H or R^(16d);

Y^(d) is —COR^(19d);

R^(16d) is selected from:

—N(R^(20d))—C(═O)—O—R^(17d),

—N(R^(20d))—C(═O)—R^(17d),

—N(R^(20d))—C(═O)—NH—R^(17d),

—N(R^(20d))SO₂—R^(17d), or

—N(R^(20d))SO₂—NR^(20d)R^(17d);

R^(17d) is selected from: C₁-C₁₀ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁ cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)aryl optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to L_(n), biaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), heteroaryl optionally substituted with a bond to L_(n), aryl optionally substituted with a bond to L_(n), or a bond to L_(n), wherein said aryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, heteroaryl, halo,cyano, amino, CF₃, and NO₂;

R^(19d) is selected from:

hydroxy, C₁-C₁₀ alkoxy,

methylcarbonyloxymethoxy-,

ethylcarbonyloxymethoxy-,

t-butylcarbonyloxymethoxy-,

cyclohexylcarbonyloxymethoxy-,

1-(methylcarbonyloxy)ethoxy-,

1-(ethylcarbonyloxy)ethoxy-,

1-(t-butylcarbonyloxy)ethoxy-,

1-(cyclohexylcarbonyloxy)ethoxy-,

i-propyloxycarbonyloxymethoxy-,

t-butyloxycarbonyloxymethoxy-,

1-(i-propyloxycarbonyloxy)ethoxy-,

1-(cyclohexyloxycarbonyloxy)ethoxy-,

1-(t-butyloxycarbonyloxy)ethoxy-,

dimethylaminoethoxy-,

diethylaminoethoxy-,

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-, or

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R^(20d) is H or CH₃;

R^(21d) is selected from COOH or (NR^(6d))₂;

m^(d) is 0 or 1;

n^(d) is 1-4; and

t^(d) is 0 or 1.

[7] In another even more preferred embodiment, the present invention provides a compound selected from the group:

2-(((4-(4-(((3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid;

2-(2-aza-2-((5-(N-(1,3-bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propyl)carbamoyl)(2-pyridyl))amino)vinyl)benzenesulfonic acid;

2-((6-((1-aza-2-(sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)-4-(N-(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)butanoic acid;

3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol -5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic acid;

2-(6-((6-((1-aza-2-(2-sulfophenyl)vinyl)-amino)(3-pyridyl))carbonylamino)hexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-propanoic acid;

2-((6-((1-aza-2-(2-sulfophenyl)vinyl)-amino)(3-pyridyl))carbonylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid;

[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]benzenesulfonic acid]-Glu(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid);

[2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]benzenesulfonic acid]-Glu-bis-[Glu(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid)(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)];

2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid};

2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-Glu{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid};

DOTA/N,N′-bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))-carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)-2-(amino)pentane-1,5-diamide conjugate;

DOTA/2-amino-4-(N-(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)butanoic acid salt;

DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate;

DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-3-(4-(phosphonooxy)phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid Conjugate;

DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-3-(4-(sulfooxy)phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid Conjugate;

DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(ethyl-3,6-O-disulfo-β-D-galactopyranosyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate;

DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(6-deoxy-β-cyclodextryl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate;

DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(ω-methoxypolyethylene(5,000)glycoxyethyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate;

2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-aminohexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid salt;

DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-6-(2-(bis (phosphonomethyl)amino)acetylamino)hexanolylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate;

DTPA adduct of 2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid;

or a pharmaceutically acceptable salt form thereof.

[8] In a further preferred embodiment, the present invention provides a kit comprising a compound of the present invention.

[9] In an even further preferred embodiment, the kit further comprises one or more ancillary ligands and a reducing agent.

[10] In a still further preferred embodiment, the ancillary ligands are tricine and TPPTS.

[11] In another still further preferred embodiment, the reducing agent is tin(II).

[12] In a second embodiment, the present invention provides a novel diagnostic or therapeutic metallopharmaceutical composition, comprising: a metal, a chelator capable of chelating the metal and a targeting moiety, wherein the targeting moiety is bound to the chelator, is a nonpeptide and binds to a receptor that is upregulated during angiogenesis and the compound has 0-1 linking groups between the targeting moiety and chelator.

[13] In another preferred embodiment, the metallopharmaceutical is a diagnostic radiopharmaceutical, the metal is a radioisotope selected from the group: ^(99m)Tc, ⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, and ⁶⁸Ga, the targeting moiety comprises an indazole and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α_(v)β₃, α_(v)β₅, α₅β₁, α₄β₁, α₁β₁, and α₂β₂ and the linking group is present between the targeting moiety and chelator.

[14] In another more preferred embodiment, the targeting moiety is an indazole and the receptor is α_(v)β₃.

[15] In another even more preferred embodiment, the radioisotope is ^(99m)Tc or ⁹⁵Tc, the radiopharmaceutical further comprises a first ancillary ligand and a second ancillary ligand capable of stabilizing the radiopharmaceutical.

[16] In another still more preferred embodiment, the radioisotope is ^(99m)Tc.

[17] In another further preferred embodiment, the radiopharmaceutical is selected from the group:

^(99m)Tc ((((4-(4-(((3-(2-(2-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid) (tricine)(TPPTS);

^(99m)Tc (2-(2-((5-(N-(1,3-bis(3-(2-(2-(3-(((4-(4-(((1carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propyl)carbamoyl)(2-pyridyl))2-diazenido) (tricine)(TPPTS);

^(99m)Tc (2-((6-(diazenido)(3-pyridyl))carbonylamino)-4-(N-(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)butanoic acid) (tricine)(TPPTS);

^(99m)Tc (2-(6-((6-(diazenido)(3-pyridyl))carbonylamino)hexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-propanoic acid) (tricine)(TPPTS);

^(99m)Tc (2-((6-(diazenido)(3-pyridyl))carbonylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (tricine)(TPPTS);

^(99m)Tc [2-[[[5-[carbonyl]-2-pyridinyl]diazenido]-Glu(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid)(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)) (tricine)(TPPTS);

^(99m)Tc ([2-[[[5-[carbonyl]-2-pyridinyl]diazenido]-Glu-bis-[Glu(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-yl))carbonyl-amino)propanoic acid)]) (tricine)(TPPTS);

[18] In another even more preferred embodiment, the radioisotope is ¹¹¹In.

[19] In another still more preferred embodiment, the radiopharmaceutical is an ¹¹¹In complex of 3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic acid

[20] In another preferred embodiment, the metallopharmaceutical is a therapeutic radiopharmaceutical, the metal is a radioisotope selected from the group: ¹⁸⁶Re, ¹⁸⁸Re, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹Pm, ⁹⁰Y, ²¹²Bi, ¹⁰³Pd, ¹⁰⁹Pd, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu, ¹⁰⁵Rh, ¹¹¹Ag, and ¹⁹²Ir, the targeting moiety is a nonpeptide and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α_(v)β₃, α_(v)β₅, α₅β₁, α₄β₁, α₁β₁, and α₂β₂ and the linking group is present between the targeting moiety and chelator.

[21] In another more preferred embodiment, the targeting moiety is an indazole and the receptor is α_(v)β₃.

[22] In another even more preferred embodiment, the radioisotope is ¹⁵³Sm.

[23] In another even more preferred embodiment, the radioisotope is ¹⁷⁷Lu.

[24] In another still more preferred embodiment, the radiopharmaceutical a ¹⁷⁷Lu complex of 3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic acid.

[25] In another even more preferred embodiment, the radioisotope is ⁹⁰Y.

[26] In another still more preferred embodiment, the radiopharmaceutical is a ⁹⁰Y complex of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic acid.

[27] In another preferred embodiment, the metallopharmaceutical is a MRI contrast agent, the metal is a paramagnetic metal ion selected from the group: Gd(III), Dy(III), Fe(III), and Mn(II), the targeting moiety is a nonpeptide and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α_(v)β₃, α_(v)β₅, α₅β₁, α₄β₁, α₁β₁, and α₂β₂ and the linking group is present between the targeting moiety and chelator.

[28] In another more preferred embodiment, the targeting moiety is an indazole and the receptor is α_(v)β₃.

[29] In another even more preferred embodiment, the metal ion is Gd(III).

[30] In another still more preferred embodiment, the contrast agent is a Gd complex of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)-phenyl)phenyl)sulfonyl)amino)propanoic acid.

[31] In another preferred embodiment, the metallopharmaceutical is a X-ray contrast agent, the metal is selected from the group: Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag, and Ir, the targeting moiety comprises an indazole, the receptor is α_(v)β₃, and the linking group is present between the targeting moiety and chelator.

[32] In another even more preferred embodiment, the present invention provides a novel method of treating rheumatoid arthritis in a patient comprising: administering a therapeutic radiopharmaceutical of the present invention capable of localizing in new angiogenic vasculature to a patient by injection or infusion.

[33] In another even more preferred embodiment, the present invention provides a novel method of treating cancer in a patient comprising: administering to a patient in need thereof a therapeutic radiopharmaceutical of the present invention by injection or infusion.

[34] In another even more preferred embodiment, the present invention provides a novel method of imaging formation of new blood vessels in a patient comprising: (1) administering a diagnostic radiopharmaceutical, a MRI contrast agent, or a X-ray contrast agent of the present invention to a patient by injection or infusion; (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.

[35] In another even more preferred embodiment, the present invention provides a novel method of imaging cancer in a patient comprising: (1) administering a diagnostic radiopharmaceutical of the present invention to a patient by injection or infusion; (2) imaging the patient using planar or SPECT gamma scintigraphy, or positron emission tomography.

[36] In another even more preferred embodiment, the present invention provides a novel method of imaging cancer in a patient comprising: (1) administering a MRI contrast agent of the present invention; and (2) imaging the patient using magnetic resonance imaging.

[37] In another even more preferred embodiment, the present invention provides a novel method of imaging cancer in a patient comprising: (1) administering a X-ray contrast agent of the present invention; and (2) imaging the patient using X-ray computed tomography.

[38] In a third embodiment, the present invention provides a novel compound capable of being used in an ultrasound contrast composition, comprising: a targeting moiety and a surfactant, wherein the targeting moiety is bound to the surfactant, is a nonpeptide, and binds to a receptor that is upregulated during angiogenesis and the compound has 0-1 linking groups between the targeting moiety and surfactant.

[39] In a preferred embodiment, the targeting moiety comprises an indazole and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α_(v)β₃, α_(v)β₅, α₅β₁, α₄β₁, α₁β₁, and α₂β₂ and the linking group is present between the targeting moiety and surfactant.

[40] In a more preferred embodiment, the receptor is the integrin α_(v)β₃ and the compound is of the formula:

(Q)_(d)—L_(n)—S_(f)

wherein, Q is a compound of Formula Ia:

and pharmaceutically acceptable salt forms thereof, wherein:

X^(1d), X^(2d), X^(3d), and X^(4d) are independently selected from nitrogen or carbon provided that at least two of X^(1d), X^(2d), X^(3d) and X^(4d) are carbon;

R^(1d) is selected from:

A^(d) and B^(d) are independently —CH₂—, —O—, —N(R^(2d))—, or —C(═O)—;

A^(1d) and B^(1d) are independently —CH₂— or —N(R^(3d))—;

D^(d) is —N(R^(2d))—, —O—, —S—, —C(═O)— or —SO₂—;

E^(d)—F^(d) is —C(R^(4d))═C(R^(5d))—, —N═C(R^(4d))—, —C(R^(4d))═N—, or —C(R^(4d))₂C(R^(5d))₂—;

J^(d), K^(d), L^(d) and M^(d) are independently selected from —C(R^(4d))—, —C(R^(5d))— or —N—, provided that at least one of J^(d), K^(d), L^(d) and M^(d) is not —N—;

R^(2d) is selected from: H, C₁-C₆ alkyl, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl; (C₁-C₆ alkyl)aminocarbonyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, heteroaryl(C₁-C₆ alkyl)carbonyl, heteroarylcarbonyl, aryl(C₁-C₆ alkyl)—, (C₁-C₆ alkyl)carbonyl—, arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl, aryloxycarbonyl, or aryl(C₁-C₆ alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro;

R^(3d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)—, or heteroaryl(C₁-C₆ alkyl)—;

R^(4d) and R^(5d) are independently selected from: H, C₁-C₄ alkoxy, NR^(2d)R^(3d), halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)—, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl, or alternatively, when substituents on adjacent atoms, R^(4d) and R^(5d) can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃, or NO₂;

U^(d) is selected from:

—(CH₂)_(n) ^(d)—,

—(CH₂)_(n) ^(d)(CR^(7d)═CR^(8d))(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)(C═C)(CH₂)_(m) ^(d)—,

—(CH₂)_(t) ^(d)Q(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)O(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)N(R^(6d))(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)C(═O)(CH₂)_(m) ^(d)—,

—(CH₂)_(n) ^(d)(C═O)N(R^(6d))(CH₂)_(m) ^(d)—

—(CH₂)_(n) ^(d)N(R^(6d))(C═O)(CH₂)_(m) ^(d)—, or

—(CH₂)_(n) ^(d)S(O)_(p) ^(d)(CH₂)_(m) ^(d)—;

wherein one or more of the methylene groups in U^(d) is optionally substituted with R^(7d);

Q^(d) is selected from 1,2-cycloalkylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 2,4-pyridinylene, or 3,4-pyridazinylene;

R^(6d) is selected from: H, C₁-C₄ alkyl, or benzyl;

R^(7d) and R^(8d) are independently selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)—, or heteroaryl(C₀-C₆ alkyl)—;

R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), N(R^(6d))₂, halogen, NO₂, CN, CF₃, CO₂R^(17d), C(═O)R^(17d), CONR^(17d)R^(20d), —SO₂R^(17d), —SO₂NR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₆ alkenyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₇ cycloalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₄-C₁₁ cycloalkylalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), aryl substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d), or aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d);

R^(11d) is selected from H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)R^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d);

W^(d) is selected from:

—(C(R^(12d))₂)_(q) ^(d)C(═O)N(R^(13d))—, or

—C(═O)—N(R^(13d))—(C(R^(12d))₂)_(q) ^(d)—;

X^(d) is —C(R^(12d))(R^(14d))—C (R^(12d))(R^(15d))—; or alternatively, W^(d) and X^(d) can be taken together to be

R^(12d) is selected from H, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₄-C₁₀ cycloalkylalkyl, (C₁-C₄ alkyl)carbonyl, aryl, or aryl(C₁-C₆ alkyl)—;

R^(13d) is selected from H, C₁-C₆ alkyl, C₃-C₇ cycloalkylmethyl, or aryl(C₁-C₆ alkyl)—;

R^(14d) is selected from: H, C₁-C₆ alkylthio(C₁-C₆ alkyl)—, aryl(C₁-C₁₀ alkylthioalkyl)—, aryl(C₁-C₁₀ alkoxyalkyl)—, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₆ hydroxyalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)—, heteroaryl(C₁-C₆ alkyl)—, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), or CONR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0-1 R^(16d) or 0-2 R^(11d);

R^(15d) is selected from: H, R^(16d), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ alkylaminoalkyl, C₁-C₁₀ dialkylaminoalkyl, (C₁-C₁₀ alkyl)carbonyl, aryl(C₀-C₆ alkyl)carbonyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl ,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)—, heteroaryl(C₁-C₆ alkyl)—, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), CONR^(17d)R^(20d), SO₂R^(17d), or SO₂NR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0-2 R^(11d);

Y^(d) is selected from: —COR^(19d), —SO₃H, —PO₃H, tetrazolyl, —CONHNHSO₂CF₃, —CONHSO₂R^(17d), —CONHSO₂NHR^(17d), —NHCOCF₃, —NHCONHSO₂R^(17d), —NHSO₂R^(17d), —OPO₃H₂, —OSO₃H, —PO₃H₂, —SO₃H, —SO₂NHCOR^(17d), —SO₂NHCO₂R^(17d),

R^(16d) is selected from:

—N(R^(20d))—C(═O)—O—R^(17d),

—N(R^(20d))—C(═O)—R^(17d),

—N(R^(20d))—C(═O)—NH—R^(17d),

—N(R^(20d))SO₂—R^(17d), or

—N(R^(20d))SO₂—NR^(20d)R^(17d);

R^(17d) is selected from: C₁-C₁₀ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁ cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)aryl optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to L_(n), biaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), heteroaryl optionally substituted with a bond to L_(n), aryl optionally substituted with a bond to L_(n), or a bond to L_(n), wherein said aryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, heteroaryl, halo,cyano, amino, CF₃, and NO₂;

R^(18d) is selected from:

H,

—C(═O)—O—R^(17d),

—C(═O)—R^(17d),

—C(═O)—NH—R^(17d),

—SO₂—R^(17d), or

—SO₂—NR^(20d)R^(17d);

R^(19d) is selected from: hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy, aryloxy, aryl(C₁-C₆ alkoxy)—, C₃-C₁₀ alkylcarbonyloxyalkyloxy, C₃-C₁₀ alkoxycarbonyloxyalkyloxy, C₂-C₁₀ alkoxycarbonylalkyloxy, C₅-C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonylalkyloxy, C₇-C₁₁ aryloxycarbonylalkyloxy, C₈-C₁₂ aryloxycarbonyloxyalkyloxy, C₈-C₁₂ arylcarbonyloxyalkyloxy, C₅-C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅-C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀-C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R^(11d))(R^(12d))N—(C₁-C₁₀ alkoxy)—;

R^(20d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)—, or heteroaryl (C₁-C₆ alkyl)—;

R^(21d) is selected from: COOH or NR^(6d) ₂;

m^(d) is 0-4;

n^(d) is 0-4;

t^(d) is 0-4;

p^(d) is 0-2;

q^(d) is 0-2;

r^(d) is 0-2;

with the following provisos:

(1) t^(d), n^(d), m^(d) and q^(d) are chosen such that the number of atoms connecting R^(1d) and Y^(d) is in the range of 10-14; and

(2) n^(d) and m^(d) are chosen such that the value of n^(d) plus m^(d) is greater than one unless U^(d) is —(CH₂)_(t) ^(d)Q^(d)(CH₂)_(m) ^(d)—;

d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

S_(f) is a surfactant which is a lipid or a compound of the formula:

A⁹ is selected from the group: OH and OR²⁷;

A¹⁰ is OR²⁷;

R²⁷ is C(═O)C₁₋₂₀ alkyl;

E¹ is C₁₋₁₀ alkylene substituted with 1-3 R²⁸;

R²⁸ is independently selected at each occurrence from the group: R³⁰, —PO₃H—R³⁰, ═O, —CO₂R²⁹, —C(═O)R²⁹, —C(═O)N(R²⁹)₂, —CH₂OR²⁹, —OR²⁹, —N(R²⁹)₂, C₁-C₅ alkyl, and C₂-C₄ alkenyl;

R²⁹ is independently selected at each occurrence from the group: R³⁰, H, C₁-C₆ alkyl, phenyl, benzyl, and trifluoromethyl;

R³⁰ is a bond to L_(n);

L_(n) is a linking group having the formula:

(CR⁶R⁷)_(g)—(W)_(h)—(CR^(6a)R^(7a))_(g′)—(Z)_(k)—(W)_(h′)—(CR⁸R⁹)_(g″—(W)) _(h″)—(CR^(8a)R^(9a))_(g″′)

W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, (OCH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂O)₂₀₋₂₀₀, (OCH₂CH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂CH₂O)₂₀₋₂₀₀, and (aa)_(t′);

aa is independently at each occurrence an amino acid;

Z is selected from the group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁰;

R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R⁹ and R^(9a) are independently selected at each occurrence from the group: H, ═O, COOH, SO₃H, PO₃H, C₁-C₅ alkyl substituted with 0-3 R¹⁰, aryl substituted with 0-3 R¹⁰, benzyl substituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to S_(f);

R¹⁰ is independently selected at each occurrence from the group: a bond to S_(f), COOR¹¹, OH, NHR¹¹, SO₃H, PO₃H, aryl substituted with 0-3 R¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1 R¹², and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹¹;

R¹¹ is independently selected at each occurrence from the group: H, aryl substituted with 0-1 R¹², a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², amino acid substituted with 0-1 R¹², and a bond to S_(f);

R¹² is a bond to S_(f);

k is selected from 0, 1, and 2;

h is selected from 0, 1, and 2;

h′ is selected from 0, 1, 2, 3, 4, and 5;

h″ is selected from 0, 1, 2, 3, 4, and 5;

g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

g″′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

and a pharmaceutically acceptable salt thereof.

[41] In another even more preferred embodiment, the compound is of the formula:

Q—L_(n)—S_(f)

wherein:

Q is a compound of Formula IIa or IIb:

 and pharmaceutically acceptable salt forms thereof wherein:

X^(1d) and X^(3d) are independently selected from nitrogen or carbon;

R^(1d) is selected from:

 wherein the above heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH₂, halogen, NO₂, CN, CF₃, C₁-C₄ alkoxy, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl;

U^(d) is —(CH₂)_(n)—, —(CH₂)_(t) ^(d)Q^(d) (CH₂)_(m) ^(d)— or —C(═O)(CH₂)_(n) ^(d)−1—, wherein one of the methylene groups is optionally substituted with R^(7d);

Q^(d) is selected from 1,2-phenylene, 1,3-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, or 2,4-pyridinylene;

R^(6d) is selected from: H, C₁-C₄ alkyl, or benzyl;

R^(7d) is selected from: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl), heteroaryl, or heteroaryl(C₁-C₆ alkyl);

R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), halogen, CO₂R^(17d), CONR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₇ cycloalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₄-C₁₁ cycloalkylalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), or aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d);

R^(11d) is selected from: H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)R^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d);

W^(d) is —C(═O)—N(R^(13d))—;

X^(d) is —CH(R^(14d))—CH(R^(15d))—;

R¹³ ^(d) is H or CH₃;

R^(14d) is selected from: H, C₁-C₁₀ alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, halo, cyano, amino, CF₃, and NO₂;

R^(15d) is H or R^(16d);

Y^(d) is —COR^(19d);

R^(16d) is selected from:

—NH(R^(20d))—C(═O)—O—R^(17d),

—N(R^(20d))—C(═O)—R^(17d),

—N(R^(20d))—C(═O)—NH—R^(17d),

—N(R^(20d))SO₂—R^(17d), or

—N(R^(20d))SO₂—N(R^(20d))R^(17d);

R^(17d) is selected from: C₁-C₁₀ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁ cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)aryl optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to L_(n), biaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), heteroaryl optionally substituted with a bond to L_(n), aryl optionally substituted with a bond to L_(n), or a bond to L_(n), wherein said aryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, heteroaryl, halo,cyano, amino, CF₃, and NO₂;

R^(19d) is selected from:

hydroxy, C₁-C₁₀ alkoxy,

methylcarbonyloxymethoxy-,

ethylcarbonyloxymethoxy-,

t-butylcarbonyloxymethoxy-,

cyclohexylcarbonyloxymethoxy-,

1-(methylcarbonyloxy)ethoxy-,

1-(ethylcarbonyloxy)ethoxy-,

1-(t-butylcarbonyloxy)ethoxy-,

1-(cyclohexylcarbonyloxy)ethoxy-,

i-propyloxycarbonyloxymethoxy-,

t-butyloxycarbonyloxymethoxy-,

1-(i-propyloxycarbonyloxy)ethoxy-,

1-(cyclohexyloxycarbonyloxy)ethoxy-,

1-(t-butyloxycarbonyloxy)ethoxy-,

dimethylaminoethoxy-,

diethylaminoethoxy-,

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-, or

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

R^(20d) is H or CH₃;

R^(21d) is selected from COOH or (NR^(6d))₂;

m^(d) is 0 or 1;

n^(d) is 1-4;

t^(d) is 0 or 1;

S_(f) is a surfactant which is a lipid or a compound of the formula:

A⁹ is OR²⁷;

A¹⁰ is OR²⁷;

R²⁷ is C(═O)C₁₋₅ alkyl;

E¹ is C₁₋₄ alkylene substituted with 1-3 R²⁸;

R²⁸ is independently selected at each occurrence from the group: R³⁰, —PO₃H—R³⁰, ═O, —CO₂R²⁹, —C(═O)R²⁹, —CH₂OR²⁹, —OR²⁹, and C₁-C₅ alkyl;

R²⁹ is independently selected at each occurrence from the group: R³⁰, H, C₁-C₆ alkyl, phenyl, and benzyl;

R³⁰ is a bond to L_(n);

L_(n) is a linking group having the formula:

(CR⁶R⁷)_(g)—(W)_(h)—(CR^(6a)R^(7a))_(g′)—(Z)_(k)—(W)_(h′)—(CR⁸R⁹)_(g″)—(W)_(h″)—(CR^(8a)R^(9a))_(g″′)

W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, (OCH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂O)₂₀₋₂₀₀, (OCH₂CH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂CH₂O)₂₀₋₂₀₀, and (aa)_(t′);

aa is independently at each occurrence an amino acid;

Z is selected from the group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁰;

R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R⁹ and R^(9a) are independently selected at each occurrence from the group: H, ═O, C₁-C₅ alkyl substituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3 R¹⁰, and a bond to S_(f);

R¹⁰ is independently selected at each occurrence from the group: a bond to S_(f), COOR¹¹, OH, NHR¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², and C₁₋₅ alkoxy substituted with 0-1 R¹²;

R¹¹ is independently selected at each occurrence from the group: H, aryl substituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², amino acid substituted with 0-1 R¹², and a bond to S_(f);

R¹² is a bond to S_(f);

k is selected from 0, 1, and 2;

h is selected from 0, 1, and 2;

h′ is selected from 0, 1, 2, 3, 4, and 5;

h″ is selected from 0, 1, 2, 3, 4, and 5;

g is selected from 0, 1, 2, 3, 4, and 5;

g′ is selected from 0, 1, 2, 3, 4, and 5;

g″ is selected from 0, 1, 2, 3, 4, and 5;

g″′ is selected from 0, 1, 2, 3, 4, and 5;

s is selected from 0, 1, 2, 3, 4, and 5;

s′ is selected from 0, 1, 2, 3, 4, and 5;

s″ is selected from 0, 1, 2, 3, 4, and 5;

t is selected from 0, 1, 2, 3, 4, and 5;

t′ is selected from 0, 1, 2, 3, 4, and 5;

and a pharmaceutically acceptable salt thereof.

[42] In another still more preferred embodiment, the present invention provides a compound selected from the group:

DPPE-2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid-dodecanoate conjugate;

ω-amino-PEG₃₄₀₀-2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid; and

ω-amino-PEG₃₄₀₀-Glu-(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)-propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)₂.

[43] In another even more preferred embodiment, the present invention provides a novel ultrasound contrast agent composition, comprising:

(a) a compound comprising: an indazole that binds to the integrin α_(v)β₃, a surfactant and a linking group between the indazole and the surfactant;

(b) a parenterally acceptable carrier; and,

(c) an echogenic gas.

[44] In another still more preferred embodiment, the ultrasound contrast agent further comprises: 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, and N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine.

[45] In another further preferred embodiment, the echogenic gas is a C₂₋₅ perfluorocarbon.

[46] In another even more preferred embodiment, the present invention provides a method of imaging cancer in a patient comprising: (1) administering, by injection or infusion, a ultrasound contrast agent composition of the present invention to a patient; and (2) imaging the patient using sonography.

[47] In another even more preferred embodiment, the present invention provides a novel method of imaging formation of new blood vessels in a patient comprising: (1) administering, by injection or infusion, a ultrasound contrast agent composition of the present invention to a patient; (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.

[48] In another even more preferred embodiment, the present invention provides a novel therapeutic radiopharmaceutical composition, comprising:

(a) a therapeutic radiopharmaceutical of the present invention; and,

(b) a parenterally acceptable carrier.

[49] In another even more preferred embodiment, the present invention provides a novel therapeutic radiopharmaceutical composition, comprising:

(a) a diagnostic radiopharmaceutical, a MRI contrast agent, or a X-ray contrast agent of the present invention; and,

(b) a parenterally acceptable carrier.

Another embodiment of the present invention is diagnostic kits for the preparation of radiopharmaceuticals useful as imaging agents for cancer or imaging agents for imaging formation of new blood vessels. Diagnostic kits of the present invention comprise one or more vials containing the sterile, non-pyrogenic, formulation comprised of a predetermined amount of a reagent of the present invention, and optionally other components such as one or two ancillary ligands, reducing agents, transfer ligands, buffers, lyophilization aids, stabilization aids, solubilization aids and bacteriostats. The inclusion of one or more optional components in the formulation will frequently improve the ease of synthesis of the radiopharmaceutical by the practicing end user, the ease of manufacturing the kit, the shelf-life of the kit, or the stability and shelf-life of the radiopharmaceutical. The inclusion of one or two ancillary ligands is required for diagnostic kits comprising reagent comprising a hydrazine or hydrazone bonding moiety. The one or more vials that contain all or part of the formulation can independently be in the form of a sterile solution or a lyophilized solid.

Another aspect of the present invention are diagnostic kits for the preparation of radiopharmaceuticals useful as imaging agents for cancer. Diagnostic kits of the present invention comprise one or more vials containing the sterile, non-pyrogenic, formulation comprised of a predetermined amount of a reagent of the present invention, and optionally other components such as one or two ancillary ligands, reducing agents, transfer ligands, buffers, lyophilization aids, stabilization aids, solubilization aids and bacteriostats. The inclusion of one or more optional components in the formulation will frequently improve the ease of synthesis of the radiopharmaceutical by the practicing end user, the ease of manufacturing the kit, the shelf-life of the kit, or the stability and shelf-life of the radiopharmaceutical. The inclusion of one or two ancillary ligands is required for diagnostic kits comprising reagent comprising a hydrazine or hydrazone bonding moiety. The one or more vials that contain all or part of the formulation can independently be in the form of a sterile solution or a lyophilized solid.

Another aspect of the present invention contemplates a method of imaging cancer in a patient involving: (1) synthesizing a diagnostic radiopharmaceutical of the present invention, using a reagent of the present invention, capable of localizing in tumors; (2) administering said radiopharmaceutical to a patient by injection or infusion; (3) imaging the patient using planar or SPECT gamma scintigraphy, or positron emission tomography.

Another aspect of the present invention contemplates a method of imaging cancer in a patient involving: (1) administering a paramagnetic metallopharmaceutical of the present invention capable of localizing in tumors to a patient by injection or infusion; and (2) imaging the patient using magnetic resonance imaging.

Another aspect of the present invention contemplates a method of imaging cancer in a patient involving: (1) administering a X-ray contrast agent of the present invention capable of localizing in tumors to a patient by injection or infusion; and (2) imaging the patient using X-ray computed tomography.

Another aspect of the present invention contemplates a method of imaging cancer in a patient involving: (1) administering a ultrasound contrast agent of the present invention capable of localizing in tumors to a patient by injection or infusion; and (2) imaging the patient using sonography.

Another aspect of the present invention contemplates a method of treating cancer in a patient involving: (1) administering a therapeutic radiopharmaceutical of the present invention capable of localizing in tumors to a patient by injection or infusion.

DEFINITIONS

The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention contain asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Two distinct isomers (cis and trans) of the peptide bond are known to occur; both can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The D and L-isomers of a particular amino acid are designated herein using the conventional 3-letter abbreviation of the amino acid, as indicated by the following examples: D-Leu, or L-Leu.

When any variable occurs more than one time in any substituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁵², then said group may optionally be substituted with up to two R⁵², and R⁵² at each occurrence is selected independently from the defined list of possible R⁵². Also, by way of example, for the group —N(R⁵³)₂, each of the two R⁵³ substituents on N is independently selected from the defined list of possible R⁵³. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring.

The term “nonpeptide” means preferably less than three amide bonds in the backbone core of the targeting moiety or preferably less than three amino acids or amino acid mimetics in the targeting moiety.

The term “metallopharmaceutical” means a pharmaceutical comprising a metal. The metal is the cause of the imageable signal in diagnostic applications and the source of the cytotoxic radiation in radiotherapeutic applications. Radiopharmaceuticals are metallopharmaceuticals in which the metal is a radioisotope.

By “reagent” is meant a compound of this invention capable of direct transformation into a metallopharmaceutical of this invention. Reagents may be utilized directly for the preparation of the metallopharmaceuticals of this invention or may be a component in a kit of this invention.

The term “binding agent” means a metallopharmaceutical of this invention having affinity for and capable of binding to the vitronectin receptor. The binding agents of this invention have Ki<1000nM. By “stable compound” or “stable structure” is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious pharmaceutical agent.

The term “substituted”, as used herein, means that one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's or group's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

The term “bond”, as used herein, means either a single or double bond.

The term “salt”, as used herein, is used as defined in the CRC Handbook of Chemistry and Physics, 65th Edition, CRC Press, Boca Raton, Fla., 1984, as any substance which yields ions, other than hydrogen or hydroxyl ions. As used herein, “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds modified by making acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl; “cycloalkyl” or “carbocycle” is intended to include saturated and partially unsaturated ring groups, including mono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl; “bicycloalkyl” or “bicyclic” is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth.

As used herein, the term “alkene” or “alkenyl” is intended to include hydrocarbon chains having the specified number of carbon atoms of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.

As used herein, the term “alkyne” or “alkynyl” is intended to include hydrocarbon chains having the specified number of carbon atoms of either a straight or branched configuration and one or more unsaturated carbon-carbon triple bonds which may occur in any stable point along the chain, such as propargyl, and the like.

As used herein, “aryl” or “aromatic residue” is intended to mean phenyl or naphthyl, which when substituted, the substitution can be at any position.

As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, the term “alkaryl” means an aryl group bearing an alkyl group of 1-10 carbon atoms; the term “aralkyl” means an alkyl group of 1-10 carbon atoms bearing an aryl group; the term “arylalkaryl” means an aryl group bearing an alkyl group of 1-10 carbon atoms bearing an aryl group; and the term “heterocycloalkyl” means an alkyl group of 1-10 carbon atoms bearing a heterocycle.

A “polyalkylene glycol” is a polyethylene glycol, polypropylene glycol or polybutylene glycol having a molecular weight of less than about 5000, terminating in either a hydroxy or alkyl ether moiety.

A “carbohydrate” is a polyhydroxy aldehyde, ketone, alcohol or acid, or derivatives thereof, including polymers thereof having polymeric linkages of the acetal type.

A “cyclodextrin” is a cyclic oligosaccharide. Examples of cyclodextrins include, but are not limited to, α-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2,6 di-O-methyl-β-cyclodextrin, sulfated-β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, and sulfated γ-cyclodextrin.

As used herein, the term “polycarboxyalkyl” means an alkyl group having between two and about 100 carbon atoms and a plurality of carboxyl substituents; and the term “polyazaalkyl” means a linear or branched alkyl group having between two and about 100 carbon atoms, interrupted by or substituted with a plurality of amine groups.

A “reducing agent” is a compound that reacts with a radionuclide, which is typically obtained as a relatively unreactive, high oxidation state compound, to lower its oxidation state by transferring electron(s) to the radionuclide, thereby making it more reactive. Reducing agents useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals include but are not limited to stannous chloride, stannous fluoride, formamidine sulfinic acid, ascorbic acid, cysteine, phosphines, and cuprous or ferrous salts. Other reducing agents are described in Brodack et. al., PCT Application 94/22496, which is incorporated herein by reference.

A “transfer ligand” is a ligand that forms an intermediate complex with a metal ion that is stable enough to prevent unwanted side-reactions but labile enough to be converted to a metallopharmaceutical. The formation of the intermediate complex is kinetically favored while the formation of the metallopharmaceutical is thermodynamically favored. Transfer ligands useful in the preparation of metallopharmaceuticals and in diagnostic kits useful for the preparation of diagnostic radiopharmaceuticals include but are not limited to gluconate, glucoheptonate, mannitol, glucarate, N,N,N′,N′-ethylenediaminetetraacetic acid, pyrophosphate and methylenediphosphonate. In general, transfer ligands are comprised of oxygen or nitrogen donor atoms.

The term “donor atom” refers to the atom directly attached to a metal by a chemical bond.

“Ancillary” or “co-ligands” are ligands that are incorporated into a radiopharmaceutical during its synthesis. They serve to complete the coordination sphere of the radionuclide together with the chelator or radionuclide bonding unit of the reagent. For radiopharmaceuticals comprised of a binary ligand system, the radionuclide coordination sphere is composed of one or more chelators or bonding units from one or more reagents and one or more ancillary or co-ligands, provided that there are a total of two types of ligands, chelators or bonding units. For example, a radiopharmaceutical comprised of one chelator or bonding unit from one reagent and two of the same ancillary or co-ligands and a radiopharmaceutical comprised of two chelators or bonding units from one or two reagents and one ancillary or co-ligand are both considered to be comprised of binary ligand systems. For radiopharmaceuticals comprised of a ternary ligand system, the radionuclide coordination sphere is composed of one or more chelators or bonding units from one or more reagents and one or more of two different types of ancillary or co-ligands, provided that there are a total of three types of ligands, chelators or bonding units. For example, a radiopharmaceutical comprised of one chelator or bonding unit from one reagent and two different ancillary or co-ligands is considered to be comprised of a ternary ligand system.

Ancillary or co-ligands useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals are comprised of one or more oxygen, nitrogen, carbon, sulfur, phosphorus, arsenic, selenium, and tellurium donor atoms. A ligand can be a transfer ligand in the synthesis of a radiopharmaceutical and also serve as an ancillary or co-ligand in another radiopharmaceutical. Whether a ligand is termed a transfer or ancillary or co-ligand depends on whether the ligand remains in the radionuclide coordination sphere in the radiopharmaceutical, which is determined by the coordination chemistry of the radionuclide and the chelator or bonding unit of the reagent or reagents.

A “chelator” or “bonding unit” is the moiety or group on a reagent that binds to a metal ion through the formation of chemical bonds with one or more donor atoms.

The term “binding site” means the site in vivo or in vitro that binds a biologically active molecule.

A “diagnostic kit” or “kit” comprises a collection of components, termed the formulation, in one or more vials which are used by the practicing end user in a clinical or pharmacy setting to synthesize diagnostic radiopharmaceuticals. The kit provides all the requisite components to synthesize and use the diagnostic radiopharmaceutical except those that are commonly available to the practicing end user, such as water or saline for injection, a solution of the radionuclide, equipment for heating the kit during the synthesis of the radiopharmaceutical, if required, equipment necessary for administering the radiopharmaceutical to the patient such as syringes and shielding, and imaging equipment.

Therapeutic radiopharmaceuticals, X-ray contrast agent pharmaceuticals, ultrasound contrast agent pharmaceuticals and metallopharmaceuticals for magnetic resonance imaging contrast are provided to the end user in their final form in a formulation contained typically in one vial, as either a lyophilized solid or an aqueous solution. The end user reconstitutes the lyophilized with water or saline and withdraws the patient dose or just withdraws the dose from the aqueous solution formulation as provided.

A “lyophilization aid” is a component that has favorable physical properties for lyophilization, such as the glass transition temperature, and is added to the formulation to improve the physical properties of the combination of all the components of the formulation for lyophilization.

A “stabilization aid” is a component that is added to the metallopharmaceutical or to the diagnostic kit either to stabilize the metallopharmaceutical or to prolong the shelf-life of the kit before it must be used. Stabilization aids can be antioxidants, reducing agents or radical scavengers and can provide improved stability by reacting preferentially with species that degrade other components or the metallopharmaceutical.

A “solubilization aid” is a component that improves the solubility of one or more other components in the medium required for the formulation.

A “bacteriostat” is a component that inhibits the growth of bacteria in a formulation either during its storage before use of after a diagnostic kit is used to synthesize a radiopharmaceutical.

The following abbreviations are used herein:

Acm acetamidomethyl b-Ala, beta-Ala 3-aminopropionic acid or bAla ATA 2-aminothiazole-5-acetic acid or 2- aminothiazole-5-acetyl group Boc t-butyloxycarbonyl CBZ, Cbz or Z Carbobenzyloxy Cit citrulline Dap 2,3-diaminopropionic acid DCC dicyclohexylcarbodiimide DIEA diisopropylethylamine DMAP 4-dimethylaminopyridine EOE ethoxyethyl HBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate hynic boc-hydrazinonicotinyl group or 2-[[[5- [carbonyl]-2-pyridinyl]hydrazono]methyl]- benzenesulfonic acid, NMeArg or MeArg a-N-methyl arginine NMeAsp a-N-methyl aspartic acid NMM N-methylmorpholine OcHex O-cyclohexyl OBzl O-benzyl oSu O-succinimidyl TBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3- tetramethyluronium tetrafluoroborate THF tetrahydrofuranyl THP tetrahydropyranyl Tos tosyl Tr trityl

The following conventional three-letter amino acid abbreviations are used herein; the conventional one-letter amino acid abbreviations are NOT used herein:

Ala alanine Arg arginine Asn asparagine Asp aspartic acid Gys cysteine Gln glutamine Glu glutamic acid Gly glycine His histidine Ile isoleucine Leu leucine Lys lysine Met methionine Nle norleucine Orn ornithine Phe phenylalanine Phg phenylglycine Pro proline Sar sarcosine Ser serine Thr threonine Trp tryptophan Tyr tyrosine Val valine

As used herein, the term “bubbles”, as used herein, refers to vesicles which are generally characterized by the presence of one or more membranes or walls surrounding an internal void that is filled with a gas or precursor thereto. Exemplary bubbles include, for example, liposomes, micelles and the like.

As used herein, the term “lipid” refers to a synthetic or naturally-occurring amphipathic compound which comprises a hydrophilic component and a hydrophobic component. Lipids include, for example, fatty acids, neutral fats, phosphatides, glycolipids, aliphatic alchols and waxes, terpenes and steroids.

As used herein, the term “lipid composition” refers to a composition which comprises a lipid compound. Exemplary lipid compositions include suspensions, emulsions and vesicular compositions.

As used herein, the term “lipid formulation” refers to a composition which comprises a lipid compound and a bioactive agent.

As used herein, the term “vesicle” refers to a spherical entity which is characterized by the presence of an internal void. Preferred vesicles are formulated from lipids, including the various lipids described herein. In any given vesicle, the lipids may be in the form of a monolayer or bilayer, and the mono- or bilayer lipids may be used to form one of more mono- or bilayers. In the case of more than one mono- or bilayer, the mono- or bilayers are generally concentric. The lipid vesicles described herein include such entities commonly referred to as liposomes, micelles, bubbles, microbubbles, microspheres and the like. Thus, the lipids may be used to form a unilamellar vesicle (comprised of one monolayer or bilayer), an oligolamellar vesicle (comprised of about two or about three monolayers or bilayers) or a multilamellar vesicle (comprised of more than about three monolayers or bilayers). The internal void of the vesicles may be filled with a liquid, including, for example, an aqueous liquid, a gas, a gaseous precursor, and/or a solid or solute material, including, for example, a bioactive agent, as desired.

As used herein, the term “vesicular composition” refers to a composition which is formulate from lipids and which comprises vesicles.

As used herein, the term “vesicle formulation” refers to a composition which comprises vesicles and a bioactive agent.

As used herein, the term “lipsomes” refers to a generally spherical cluster or aggregate of amphipathic compounds, including lipid compounds, typically in the form of one or more concentric layers, for example, bilayers. They may also be referred to herein as lipid vesicles.

Angiogenesis is the process of formation of new capillary blood vessels from existing vasculature. It is an important component of a variety of physiological processes including ovulation, embryonic development, wound repair, and collateral vascular generation in the myocardium. It is also central to a number of pathological conditions such as tumor growth and metastasis, diabetic retinopathy, and macular degeneration. The process begins with the activation of existing vascular endothelial cells in response to a variety of cytokines and growth factors. The activated endothelial cells secrete enzymes that degrade the basement membrane of the vessels. The endothelial cells then proliferate and migrate into the extracellular matrix first forming tubules and subsequently new blood vessels.

Under normal conditions, endothelial cell proliferation is a very slow process, but it increases for a short period of time during embryogenesis, ovulation and wound healing. This temporary increase in cell turnover is governed by a combination of a number of growth stimulatory factors and growth suppressing factors. In pathological angiogenesis, this normal balance is disrupted resulting in continued increased endothelial cell proliferation. Some of the pro-angiogenic factors that have been identified include basic fibroblast growth factor (bFGF), angiogenin, TGF-alpha, TGF-beta, and vascular endothelium growth factor (VEGF), while interferon-alpha, interferon-beta and thrombospondin are examples of angiogenesis suppressors.

Angiogenic factors interact with endothelial cell surface receptors such as the receptor tyrosine kinases EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, and Axl. The receptors Flk-1/KDR, neuropilin-1, and Flt-1 recognize VEGF and these interactions play key roles in VEGF-induced angiogenesis. The Tie subfamily of receptor tyrosine kinases are also expressed prominently during blood vessel formation.

The proliferation and migration of endothelial cells in the extracellular matrix is mediated by interaction with a variety of cell adhesion molecules. Integrins are a diverse family of heterodimeric cell surface receptors by which endothelial cells attach to the extracellular matrix, each other and other cells. Angiogenesis induced by bFGF or TNF-alpha depend on the agency of the integrin avb3, while angiogenesis induced by VEGF depends on the integrin avb5 (Cheresh et. al., Science, 1995, 270, 1500-2). Induction of expression of the integrins a1b1 and a2b1 on the endothelial cell surface is another important mechanism by which VEGF promotes angiogenesis (Senger, et. al., Proc. Natl. Acad, Sci USA, 1997, 94, 13612-7).

The pharmaceuticals of the present invention are comprised of a non-peptide targeting moiety for the vitronectin receptor that is expressed or upregulated in angiogenic tumor vasculature.

The ultrasound contrast agents of the present invention comprise a plurality of vitronectin receptor targeting moieties attached to or incorporated into a microbubble of a biocompatible gas, a liquid carrier, and a surfactant microsphere, further comprising an optional linking moiety, L_(n), between the targeting moieties and the microbubble. In this context, the term liquid carrier means aqueous solution and the term surfactant means any amphiphilic material which produces a reduction in interfacial tension in a solution. A list of suitable surfactants for forming surfactant microspheres is disclosed in EP0727225A2, herein incorporated by reference. The term surfactant microsphere includes nanospheres, liposomes, vesicles and the like. The biocompatible gas can be air, or a fluorocarbon, such as a C₃-C₅ perfluoroalkane, which provides the difference in echogenicity and thus the contrast in ultrasound imaging. The gas is encapsulated or contained in the microsphere to which is attached the biodirecting group, optionally via a linking group. The attachment can be covalent, ionic or by van der Waals forces. Specific examples of such contrast agents include lipid encapsulated perfluorocarbons with a plurality of tumor neovasculature receptor binding peptides, polypeptides or peptidomimetics.

X-ray contrast agents of the present invention are comprised of one or more vitronectin receptor targeting moieties attached to one or more X-ray absorbing or “heavy” atoms of atomic number 20 or greater, further comprising an optional linking moiety, L_(n), between the targeting moieties and the X-ray absorbing atoms. The frequently used heavy atom in X-ray contrast agents is iodine. Recently, X-ray contrast agents comprised of metal chelates (Wallace, R., U.S. Pat. No. 5,417,959) and polychelates comprised of a plurality of metal ions (Love, D., U.S. Pat. No. 5,679,810) have been disclosed. More recently, multinuclear cluster complexes have been disclosed as X-ray contrast agents (U.S. Pat. No. 5,804,161, PCT WO91/14460, and PCT WO 92/17215).

MRI contrast agents of the present invention are comprised of one or more vitronectin receptor targeting moieties attached to one or more paramagnetic metal ions, further comprising an optional linking moiety, L_(n), between the targeting moieties and the paramagnetic metal ions. The paramagnetic metal ions are present in the form of metal complexes or metal oxide particles. U.S. Pat. Nos. 5,412,148, and 5,760,191, describe examples of chelators for paramagnetic metal ions for use in MRI contrast agents. U.S. Pat. Nos. 5,801,228, 5,567,411, and 5,281,704, describe examples of polychelants useful for complexing more than one paramagnetic metal ion for use in MRI contrast agents. U.S. Pat. No. 5,520,904, describes particulate compositions comprised of paramagnetic metal ions for use as MRI contrast agents.

The pharmaceuticals of the present invention have the formulae, (Q)_(d)—L_(n)—(C_(h)—X), (Q)_(d)—L_(n)—(C_(h)—X¹)_(d′), (Q)_(d)—L_(n)—(X²)_(d″), and (Q)_(d)—L_(n)—(X³), wherein Q represents a non-peptide that binds to a receptor expressed in angiogenic tumor vasculature, d is 1-10, L_(n) represents an optional linking group, C_(h) represents a metal chelator or bonding moiety, X represents a radioisotope, X¹ represents paramagnetic metal ion, X² represents a paramagnetic metal ion or heavy atom containing insoluble solid particle, d″ is 1-100, and X³ represents a surfactant microsphere of an echogenic gas. The interaction of the non-peptide recognition sequences of the vitronectin receptor binding portion of the pharmaceuticals with the αvβ3 receptor results in localization of the pharmaceuticals in angiogenic tumor vasculature, which express the αvβ3 receptor.

The pharmaceuticals of the present invention can be synthesized by several approaches. One approach involves the synthesis of the targeting non-peptide moiety, Q, and direct attachment of one or more moieties, Q, to one or more metal chelators or bonding moieties, C_(h), or to a paramagnetic metal ion or heavy atom containing solid particle, or to an echogenic gas microbubble. Another approach involves the attachment of one or more moieties, Q, to the linking group, L_(n), which is then attached to one or more metal chelators or bonding moieties, C_(h), or to a paramagnetic metal ion or heavy atom containing solid particle, or to an echogenic gas microbubble. Another approach involves the synthesis of a non-peptide, Q, bearing a fragment of the linking group, L_(n), one or more of which are then attached to the remainder of the linking group and then to one or more metal chelators or bonding moieties, C_(h), or to a paramagnetic metal ion or heavy atom containing solid particle, or to an echogenic gas microbubble.

The non-peptide vitronectin binding moieties, Q, optionally bearing a linking group, L_(n), or a fragment of the linking group, can be synthesized using standard synthetic methods known to those skilled in the art. Preferred methods include but are not limited to those methods described below.

The attachment of linking groups, L_(n), to the non-peptides, Q; chelators or bonding units, C_(h), to the non-peptides, Q, or to the linking groups, L_(n); and non-peptides, bearing a fragment of the linking group to the remainder of the linking group, in combination forming the moiety, (Q)_(d)—L_(n), and then to the moiety C_(h); can all be performed by standard techniques. These include, but are not limited to, amidation, esterification, alkylation, and the formation of ureas or thioureas. Procedures for performing these attachments can be found in Brinkley, M., Bioconjugate Chemistry 1992, 3(1), which is incorporated herein by reference.

A number of methods can be used to attach the non-peptides, Q, to paramagnetic metal ion or heavy atom containing solid particles, X², by one of skill in the art of the surface modification of solid particles. In general, the targeting moiety Q or the combination (Q)_(d)L_(n) is attached to a coupling group that react with a constituent of the surface of the solid particle. The coupling groups can be any of a number of silanes which react with surface hydroxyl groups on the solid particle surface, as described in U.S. Application No. 60092360, and can also include polyphosphonates, polycarboxylates, polyphosphates or mixtures thereof which couple with the surface of the solid particles, as described in U.S. Pat. No. 5,520,904.

A number of reaction schemes can be used to attach the non-peptides, Q, to the surfactant microsphere, X³. These are illustrated in following reaction schemes where S_(f) represents a surfactant moiety that forms the surfactant microsphere.

Acylation Reaction

Y is a leaving group or active ester

Disulfide Coupling

S_(f)—SH+Q—SH→S_(f)—S—S—Q

Sulfonamide Coupling

S_(f)—S(═O)₂—Y+Q—NH₂→S_(f)—S(═O)₂—NH—Q

Reductive Amidation

 S_(f)—CHO+Q—NH₂→S_(f)—NH—Q

In these reaction schemes, the substituents S_(f) and Q can be reversed as well.

The linking group L_(n) can serve several roles. First it provides a spacing group between the metal chelator or bonding moiety, C_(h), the paramagnetic metal ion or heavy atom containing solid particle, X², and the surfactant microsphere, X³, and the one or more of the non-peptides, Q, so as to minimize the possibility that the moieties C_(h)—X, C_(h)—X¹, X², and X³, will interfere with the interaction of the recognition sequences of Q with angiogenic tumor vasculature receptors. The necessity of incorporating a linking group in a reagent is dependent on the identity of Q, C_(h)—X, C_(h)—X¹, X², and X³. If C_(h)—X, C_(h)—X¹, X², and X³, cannot be attached to Q without substantially diminishing its affinity for the receptors, then a linking group is used. A linking group also provides a means of independently attaching multiple non-peptides, Q, to one group that is attached to C_(h)—X, C_(h)—X¹, X², or X³.

The linking group also provides a means of incorporating a pharmacokinetic modifier into the pharmaceuticals of the present invention. The pharmacokinetic modifier serves to direct the biodistibution of the injected pharmaceutical other than by the interaction of the targeting moieties, Q, with the vitronectin receptors expressed in the tumor neovasculature. A wide variety of functional groups can serve as pharmacokinetic modifiers, including, but not limited to, carbohydrates, polyalkylene glycols, peptides or other polyamino acids, and cyclodextrins. The modifiers can be used to enhance or decrease hydrophilicity and to enhance or decrease the rate of blood clearance. The modifiers can also be used to direct the route of elimination of the pharmaceuticals. Preferred pharmacokinetic modifiers are those that result in moderate to fast blood clearance and enhanced renal excretion.

The metal chelator or bonding moiety, C_(h), is selected to form stable complexes with the metal ion chosen for the particular application. Chelators or bonding moieties for diagnostic radiopharmaceuticals are selected to form stable complexes with the radioisotopes that have imageable gamma ray or positron emissions, such as ^(99m)Tc, ⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁰CU, ⁶⁴CU, ⁶⁷Ga, ⁶⁸Ga, 86Y.

Chelators for technetium, copper and gallium isotopes are selected from diaminedithiols, monoamine-monoamidedithiols, triamide-monothiols, monoamine-diamide-monothiols, diaminedioximes, and hydrazines. The chelators are generally tetradentate with donor atoms selected from nitrogen, oxygen and sulfur. Preferred reagents are comprised of chelators having amine nitrogen and thiol sulfur donor atoms and hydrazine bonding units. The thiol sulfur atoms and the hydrazines may bear a protecting group which can be displaced either prior to using the reagent to synthesize a radiopharmaceutical or preferably in situ during the synthesis of the radiopharmaceutical.

Exemplary thiol protecting groups include those listed in Greene and Wuts, “Protective Groups in Organic Synthesis” John Wiley & Sons, New York (1991), the disclosure of which is hereby incorporated by reference. Any thiol protecting group known in the art can be used. Examples of thiol protecting groups include, but are not limited to, the following: acetamidomethyl, benzamidomethyl, 1-ethoxyethyl, benzoyl, and triphenylmethyl.

Exemplary protecting groups for hydrazine bonding units are hydrazones which can be aldehyde or ketone hydrazones having substituents selected from hydrogen, alkyl, aryl and heterocycle. Particularly preferred hydrazones are described in co-pending U.S. Ser. No. 08/476,296 the disclosure of which is herein incorporated by reference in its entirety.

The hydrazine bonding unit when bound to a metal radionuclide is termed a hydrazido, or diazenido group and serves as the point of attachment of the radionuclide to the remainder of the radiopharmaceutical. A diazenido group can be either terminal (only one atom of the group is bound to the radionuclide) or chelating. In order to have a chelating diazenido group at least one other atom of the group must also be bound to the radionuclide. The atoms bound to the metal are termed donor atoms.

Chelators for ¹¹¹In and ⁸⁶Y are selected from cyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, DO3A, 2-benzyl-DOTA, alpha-(2-phenethyl)1,4,7,10-tetraazazcyclododecane-1-acetic-4,7,10-tris(methylacetic)acid, 2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl-6-methyl-DTPA, and 6,6″-bis[N,N,N″,N″-tetra(carboxymethyl)aminomethyl)-4′-(3-amino-4-methoxyphenyl)-2,2′:6′,2″-terpyridine. Procedures for synthesizing these chelators that are not commercially available can be found in Brechbiel, M. and Gansow, O., J. Chem. Soc. Perkin Trans. 1992, 1, 1175; Brechbiel, M. and Gansow, O., Bioconjugate Chem. 1991, 2, 187; Deshpande, S., et. al., J. Nucl. Med. 1990, 31, 473; Kruper, J., U.S. Pat. No. 5,064,956, and Toner, J., U.S. Pat. No. 4,859,777, the disclosures of which are hereby incorporated by reference in their entirety.

The coordination sphere of metal ion includes all the ligands or groups bound to the metal. For a transition metal radionuclide to be stable it typically has a coordination number (number of donor atoms) comprised of an integer greater than or equal to 4 and less than or equal to 8; that is there are 4 to 8 atoms bound to the metal and it is said to have a complete coordination sphere. The requisite coordination number for a stable radionuclide complex is determined by the identity of the radionuclide, its oxidation state, and the type of donor atoms. If the chelator or bonding unit does not provide all of the atoms necessary to stabilize the metal radionuclide by completing its coordination sphere, the coordination sphere is completed by donor atoms from other ligands, termed ancillary or co-ligands, which can also be either terminal or chelating.

A large number of ligands can serve as ancillary or co-ligands, the choice of which is determined by a variety of considerations such as the ease of synthesis of the radiopharmaceutical, the chemical and physical properties of the ancillary ligand, the rate of formation, the yield, and the number of isomeric forms of the resulting radiopharmaceuticals, the ability to administer said ancillary or co-ligand to a patient without adverse physiological consequences to said patient, and the compatibility of the ligand in a lyophilized kit formulation. The charge and lipophilicity of the ancillary ligand will effect the charge and lipophilicity of the radiopharmaceuticals. For example, the use of 4,5-dihydroxy-1,3-benzene disulfonate results in radiopharmaceuticals with an additional two anionic groups because the sulfonate groups will be anionic under physiological conditions. The use of N-alkyl substituted 3,4-hydroxypyridinones results in radiopharmaceuticals with varying degrees of lipophilicity depending on the size of the alkyl substituents.

Preferred technetium radiopharmaceuticals of the present invention are comprised of a hydrazido or diazenido bonding unit and an ancillary ligand, A_(L1), or a bonding unit and two types of ancillary A_(L1) and A_(L2), or a tetradentate chelator comprised of two nitrogen and two sulfur atoms. Ancillary ligands A_(L1) are comprised of two or more hard donor atoms such as oxygen and amine nitrogen (sp³ hybridized). The donor atoms occupy at least two of the sites in the coordination sphere of the radionuclide metal; the ancillary ligand A_(L1) serves as one of the three ligands in the ternary ligand system. Examples of ancillary ligands A_(L1) include but are not limited to dioxygen ligands and functionalized aminocarboxylates. A large number of such ligands are available from commercial sources.

Ancillary dioxygen ligands include ligands that coordinate to the metal ion through at least two oxygen donor atoms. Examples include but are not limited to: glucoheptonate, gluconate, 2-hydroxyisobutyrate, lactate, tartrate, mannitol, glucarate, maltol, Kojic acid, 2,2-bis(hydroxymethyl)propionic acid, 4,5-dihydroxy-1,3-benzene disulfonate, or substituted or unsubstituted 1,2 or 3,4 hydroxypyridinones. (The names for the ligands in these examples refer to either the protonated or non-protonated forms of the ligands.)

Functionalized aminocarboxylates include ligands that have a combination of amine nitrogen and oxygen donor atoms. Examples include but are not limited to: iminodiacetic acid, 2,3-diaminopropionic acid, nitrilotriacetic acid, N,N′-ethylenediamine diacetic acid, N,N,N′-ethylenediamine triacetic acid, hydroxyethylethylenediamine triacetic acid, and N,N′-ethylenediamine bis-hydroxyphenylglycine. (The names for the ligands in these examples refer to either the protonated or non-protonated forms of the ligands.)

A series of functionalized aminocarboxylates are disclosed by Bridger et. al. in U.S. Pat. No. 5,350,837, herein incorporated by reference, that result in improved rates of formation of technetium labeled hydrazino modified proteins. We have determined that certain of these aminocarboxylates result in improved yields of the radiopharmaceuticals of the present invention. The preferred ancillary ligands A_(L1) functionalized aminocarboxylates that are derivatives of glycine; the most preferred is tricine (tris(hydroxymethyl)methylglycine).

The most preferred technetium radiopharmaceuticals of the present invention are comprised of a hydrazido or diazenido bonding unit and two types of ancillary designated A_(L1) and A_(L2), or a diaminedithiol chelator. The second type of ancillary ligands A_(L2) are comprised of one or more soft donor atoms selected from the group: phosphine phosphorus, arsine arsenic, imine nitrogen (sp² hybridized), sulfur (sp² hybridized) and carbon (sp hybridized); atoms which have p-acid character. Ligands A_(L2) can be monodentate, bidentate or tridentate, the denticity is defined by the number of donor atoms in the ligand. One of the two donor atoms in a bidentate ligand and one of the three donor atoms in a tridentate ligand must be a soft donor atom. We have disclosed in co-pending U.S. Ser. No. 08/415,908, and No. 60/013360 and U.S. Ser. No. 08/646,886, the disclosures of which are herein incorporated by reference in their entirety, that radiopharmaceuticals comprised of one or more ancillary or co-ligands A_(L2) are more stable compared to radiopharmaceuticals that are not comprised of one or more ancillary ligands, A_(L2); that is, they have a minimal number of isomeric forms, the relative ratios of which do not change significantly with time, and that remain substantially intact upon dilution.

The ligands A_(L2) that are comprised of phosphine or arsine donor atoms are trisubstituted phosphines, trisubstituted arsines, tetrasubstituted diphosphines and tetrasubstituted diarsines. The ligands A_(L2) that are comprised of imine nitrogen are unsaturated or aromatic nitrogen-containing, 5 or 6-membered heterocycles. The ligands that are comprised of sulfur (sp² hybridized) donor atoms are thiocarbonyls, comprised of the moiety C═S. The ligands comprised of carbon (sp hybridized) donor atoms are isonitriles, comprised of the moiety CNR, where R is an organic radical. A large number of such ligands are available from commercial sources. Isonitriles can be synthesized as described in European Patent 0107734 and in U.S. Pat. No. 4,988,827, herein incorporated by reference.

Preferred ancillary ligands A_(L2) are trisubstituted phosphines and unsaturated or aromatic 5 or 6 membered heterocycles. The most preferred ancillary ligands A_(L2) are trisubstituted phosphines and unsaturated 5 membered heterocycles.

The ancillary ligands A_(L2) may be substituted with alkyl, aryl, alkoxy, heterocycle, aralkyl, alkaryl and arylalkaryl groups and may or may not bear functional groups comprised of heteroatoms such as oxygen, nitrogen, phosphorus or sulfur. Examples of such functional groups include but are not limited to: hydroxyl, carboxyl, carboxamide, nitro, ether, ketone, amino, ammonium, sulfonate, sulfonamide, phosphonate, and phosphonamide. The functional groups may be chosen to alter the lipophilicity and water solubility of the ligands which may affect the biological properties of the radiopharmaceuticals, such as altering the distribution into non-target tissues, cells or fluids, and the mechanism and rate of elimination from the body.

Chelators or bonding moieties for therapeutic radiopharmaceuticals are selected to form stable complexes with the radioisotopes that have alpha particle, beta particle, Auger or Coster-Kronig electron emissions, such as ¹⁸⁶Re, ¹⁸⁸Re, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹Pm, ⁹⁰Y, ²¹²Bi, ¹⁰³Pd, ¹⁰⁹Pd, ¹⁵⁹Gd, 140La, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu, ¹⁰⁵Rh, ¹¹¹Ag, and ¹⁹²Ir. Chelators for rhenium, copper, palladium, platinum, iridium, rhodium, silver and gold isotopes are selected from diaminedithiols, monoamine-monoamidedithiols, triamide-monothiols, monoamine-diamide-monothiols, diaminedioximes, and hydrazines. Chelators for yttrium, bismuth, and the lanthanide isotopes are selected from cyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, DO3A, 2-benzyl-DOTA, alpha-(2-phenethyl)1,4,7,10-tetraazacyclododecane-1-acetic-4,7,10-tris(methylacetic)acid, 2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl-6-methyl-DTPA, and 6,6″-bis[N,N,N″,N″-tetra(carboxymethyl)aminomethyl)-4′-(3-amino-4-methoxyphenyl)-2,2′:6′,2″-terpyridine.

Chelators for magnetic resonance imaging contrast agents are selected to form stable complexes with paramagnetic metal ions, such as Gd(III), Dy(III), Fe(III), and Mn(II), are selected from cyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, DO3A, 2-benzyl-DOTA, alpha-(2-phenethyl)1,4,7,10-tetraazacyclododecane-1-acetic-4,7,10-tris(methylacetic)acid, 2-benzylcyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl-6-methyl-DTPA, and 6,6″-bis[N,N,N″,N″-tetra(carboxymethyl)aminomethyl)-4′-(3-amino-4-methoxyphenyl)-2,2′:6′,2″-terpyridine.

The technetium and rhenium radiopharmaceuticals of the present invention comprised of a hydrazido or diazenido bonding unit can be easily prepared by admixing a salt of a radionuclide, a reagent of the present invention, an ancillary ligand A_(L1), an ancillary ligand A_(L2), and a reducing agent, in an aqueous solution at temperatures from 0 to 100° C. The technetium and rhenium radiopharmaceuticals of the present invention comprised of a tetradentate chelator having two nitrogen and two sulfur atoms can be easily prepared by admixing a salt of a radionuclide, a reagent of the present invention, and a reducing agent, in an aqueous solution at temperatures from 0 to 100° C.

When the bonding unit in the reagent of the present invention is present as a hydrazone group, then it must first be converted to a hydrazine, which may or may not be protonated, prior to complexation with the metal radionuclide. The conversion of the hydrazone group to the hydrazine can occur either prior to reaction with the radionuclide, in which case the radionuclide and the ancillary or co-ligand or ligands are combined not with the reagent but with a hydrolyzed form of the reagent bearing the chelator or bonding unit, or in the presence of the radionuclide in which case the reagent itself is combined with the radionuclide and the ancillary or co-ligand or ligands. In the latter case, the pH of the reaction mixture must be neutral or acidic.

Alternatively, the radiopharmaceuticals of the present invention comprised of a hydrazido or diazenido bonding unit can be prepared by first admixing a salt of a radionuclide, an ancillary ligand A_(L1), and a reducing agent in an aqueous solution at temperatures from 0 to 100° C. to form an intermediate radionuclide complex with the ancillary ligand A_(L1) then adding a reagent of the present invention and an ancillary ligand A_(L2) and reacting further at temperatures from 0 to 100° C.

Alternatively, the radiopharmaceuticals of the present invention comprised of a hydrazido or diazenido bonding unit can be prepared by first admixing a salt of a radionuclide, an ancillary ligand A_(L1), a reagent of the present invention, and a reducing agent in an aqueous solution at temperatures from 0 to 100° C. to form an intermediate radionuclide complex, and then adding an ancillary ligand A_(L2) and reacting further at temperatures from 0 to 100° C.

The technetium and rhenium radionuclides are preferably in the chemical form of pertechnetate or perrhenate and a pharmaceutically acceptable cation. The pertechnetate salt form is preferably sodium pertechnetate such as obtained from commercial Tc-99m generators. The amount of pertechnetate used to prepare the radiopharmaceuticals of the present invention can range from 0.1 mCi to 1 Ci, or more preferably from 1 to 200 mCi.

The amount of the reagent of the present invention used to prepare the technetium and rhenium radiopharmaceuticals of the present invention can range from 0.01 μg to 10 mg, or more preferably from 0.5 μg to 200 μg. The amount used will be dictated by the amounts of the other reactants and the identity of the radiopharmaceuticals of the present invention to be prepared.

The amounts of the ancillary ligands A_(L1) used can range from 0.1 mg to 1 g, or more preferably from 1 mg to 100 mg. The exact amount for a particular radiopharmaceutical is a function of identity of the radiopharmaceuticals of the present invention to be prepared, the procedure used and the amounts and identities of the other reactants. Too large an amount of A_(L1) will result in the formation of by-products comprised of technetium labeled A_(L1) without a biologically active molecule or by-products comprised of technetium labeled biologically active molecules with the ancillary ligand A_(L1) but without the ancillary ligand A_(L2). Too small an amount of A_(L1) will result in other by-products such as technetium labeled biologically active molecules with the ancillary ligand A_(L2) but without the ancillary ligand A_(L1), or reduced hydrolyzed technetium, or technetium colloid.

The amounts of the ancillary ligands A_(L2) used can range from 0.001 mg to 1 g, or more preferably from 0.01 mg to 10 mg. The exact amount for a particular radiopharmaceutical is a function of the identity of the radiopharmaceuticals of the present invention to be prepared, the procedure used and the amounts and identities of the other reactants. Too large an amount of A_(L2) will result in the formation of by-products comprised of technetium labeled A_(L2) without a biologically active molecule or by-products comprised of technetium labeled biologically active molecules with the ancillary ligand A_(L2) but without the ancillary ligand A_(L1). If the reagent bears one or more substituents that are comprised of a soft donor atom, as defined above, at least a ten-fold molar excess of the ancillary ligand A_(L2) to the reagent of formula 2 is required to prevent the substituent from interfering with the coordination of the ancillary ligand A_(L2) to the metal radionuclide.

Suitable reducing agents for the synthesis of the radiopharmaceuticals of the present invention include stannous salts, dithionite or bisulfite salts, borohydride salts, and formamidinesulfinic acid, wherein the salts are of any pharmaceutically acceptable form. The preferred reducing agent is a stannous salt. The amount of a reducing agent used can range from 0.001 mg to 10 mg, or more preferably from 0.005 mg to 1 mg.

The specific structure of a radiopharmaceutical of the present invention comprised of a hydrazido or diazenido bonding unit will depend on the identity of the reagent of the present invention used, the identity of any ancillary ligand A_(L1), the identity of any ancillary ligand A_(L2), and the identity of the radionuclide. Radiopharmaceuticals comprised of a hydrazido or diazenido bonding unit synthesized using concentrations of reagents of <100 μg/mL, will be comprised of one hydrazido or diazenido group. Those synthesized using >1 mg/mL concentrations will be comprised of two hydrazido or diazenido groups from two reagent molecules. For most applications, only a limited amount of the biologically active molecule can be injected and not result in undesired side-effects, such as chemical toxicity, interference with a biological process or an altered biodistribution of the radiopharmaceutical. Therefore, the radiopharmaceuticals which require higher concentrations of the reagents comprised in part of the biologically active molecule, will have to be diluted or purified after synthesis to avoid such side-effects.

The identities and amounts used of the ancillary ligands A_(L1) and A_(L2) will determine the values of the variables y and z. The values of y and z can independently be an integer from 1 to 2. In combination, the values of y and z will result in a technetium coordination sphere that is made up of at least five and no more than seven donor atoms. For monodentate ancillary ligands A_(L2), z can be an integer from 1 to 2; for bidentate or tridentate ancillary ligands A_(L2), z is 1. The preferred combination for monodentate ligands is y equal to 1 or 2 and z equal to 1. The preferred combination for bidentate or tridentate ligands is y equal to 1 and z equal to 1.

The indium, copper, gallium, silver, palladium, rhodium, gold, platinum, bismuth, yttrium and lanthanide radiopharmaceuticals of the present invention can be easily prepared by admixing a salt of a radionuclide and a reagent of the present invention, in an aqueous solution at temperatures from 0 to 100° C. These radionuclides are typically obtained as a dilute aqueous solution in a mineral acid, such as hydrochloric, nitric or sulfuric acid. The radionuclides are combined with from one to about one thousand equivalents of the reagents of the present invention dissolved in aqueous solution. A buffer is typically used to maintain the pH of the reaction mixture between 3 and 10.

The gadolinium, dysprosium, iron and manganese metallopharmaceuticals of the present invention can be easily prepared by admixing a salt of the paramagnetic metal ion and a reagent of the present invention, in an aqueous solution at temperatures from 0 to 100° C. These paramagnetic metal ions are typically obtained as a dilute aqueous solution in a mineral acid, such as hydrochloric, nitric or sulfuric acid. The paramagnetic metal ions are combined with from one to about one thousand equivalents of the reagents of the present invention dissolved in aqueous solution. A buffer is typically used to maintain the pH of the reaction mixture between 3 and 10.

The total time of preparation will vary depending on the identity of the metal ion, the identities and amounts of the reactants and the procedure used for the preparation. The preparations may be complete, resulting in >80% yield of the radiopharmaceutical, in 1 minute or may require more time. If higher purity metallopharmaceuticals are needed or desired, the products can be purified by any of a number of techniques well known to those skilled in the art such as liquid chromatography, solid phase extraction, solvent extraction, dialysis or ultrafiltration.

Buffers useful in the preparation of metallopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals include but are not limited to phosphate, citrate, sulfosalicylate, and acetate. A more complete list can be found in the United States Pharmacopeia.

Lyophilization aids useful in the preparation of diagnostic kits useful for the preparation of radiopharmaceuticals include but are not limited to imannitol, lactose, sorbitol, dextran, Ficoll, and polyvinylpyrrolidine(PVP).

Stabilization aids useful in the preparation of metallopharmaceuticals and in diagnostic kits useful for the preparation of radiopharmaceuticals include but are not limited to ascorbic acid, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentisic acid, and inositol.

Solubilization aids useful in the preparation of metallopharmaceuticals and in diagnostic kits useful for the preparation of radiopharmaceuticals include but are not limited to ethanol, glycerin, polyethylene glycol, propylene glycol, polyoxyethylene sorbitan monooleate, sorbitan monoloeate, polysorbates, poly(oxyethylene)poly(oxypropylene)poly(oxyethylene) block copolymers (Pluronics) and lecithin. Preferred solubilizing aids are polyethylene glycol, and Pluronics.

Bacteriostats useful in the preparation of metallopharmaceuticals and in diagnostic kits useful for the preparation of radiopharmaceuticals include but are not limited to benzyl alcohol, benzalkonium chloride, chlorbutanol, and methyl, propyl or butyl paraben.

A component in a diagnostic kit can also serve more than one function. A reducing agent can also serve as a stabilization aid, a buffer can also serve as a transfer ligand, a lyophilization aid can also serve as a transfer, ancillary or co-ligand and so forth.

The diagnostic radiopharmaceuticals are administered by intravenous injection, usually in saline solution, at a dose of 1 to 100 mCi per 70 kg body weight, or preferably at a dose of 5 to 50 mCi. Imaging is performed using known procedures.

The therapeutic radiopharmaceuticals are administered by intravenous injection, usually in saline solution, at a dose of 0.1 to 100 mCi per 70 kg body weight, or preferably at a dose of 0.5 to 5 mCi per 70 kg body weight.

The magnetic resonance imaging contrast agents of the present invention may be used in a similar manner as other MRI agents as described in U.S. Pat. Nos. 5,155,215; 5,087,440; Margerstadt et al., Magn. Reson. Med., 1986, 3, 808; Runge et al., Radiology, 1988, 166, 835; and Bousquet et al., Radiology, 1988, 166, 693. Generally, sterile aqueous solutions of the contrast agents are administered to a patient intravenously in dosages ranging from 0.01 to 1.0 mmoles per kg body weight.

For use as X-ray contrast agents, the compositions of the present invention should generally have a heavy atom concentration of 1 mM to 5 M, preferably 0.1 M to 2 M. Dosages, administered by intravenous injection, will typically range from 0.5 mmol/kg to 1.5 mmol/kg, preferably 0.8 mmol/kg to 1.2 mmol/kg. Imaging is performed using known techniques, preferably X-ray computed tomography.

The ultrasound contrast agents of the present invention are administered by intravenous injection in an amount of 10 to 30 μL of the echogenic gas per kg body weight or by infusion at a rate of approximately 3 μL/kg/min. Imaging is performed using known techniques of sonography.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Representative materials and methods that may be used in preparing the compounds of the invention are described further below.

Manual solid phase peptide synthesis was performed in 25 mL polypropylene filtration tubes purchased from BioRad Inc., or in 60 mL hour-glass reaction vessels purchased from Peptides International. Oxime resin (substitution level=0.96 mmol/g) was prepared according to published procedure (DeGrado and Kaiser, J. Org. Chem. 1980, 45, 1295), or was purchased from Novabiochem (substitution level=0.62 mmol/g). 1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxylic acid was synthesized as described in U.S. Pat. No. 5,760,028. All chemicals and solvents (reagent grade) were used as supplied from the vendors cited without further purification. t-Butyloxycarbonyl (Boc) amino acids and other starting amino acids may be obtained commercially from Bachem Inc., Bachem Biosciences Inc. (Philadelphia, Pa.), Advanced ChemTech (Louisville, Ky.), Peninsula Laboratories (Belmont, Calif.), or Sigma (St. Louis, Mo.). 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and TBTU were purchased from Advanced ChemTech. N-methylmorpholine (NMM), m-cresol, D-2-aminobutyric acid (Abu), trimethylacetylchloride, diisopropylethylamine (DIEA), 1,2,4-triazole, stannous chloride dihydrate, and tris(3-sulfonatophenyl)phosphine trisodium salt (TPPTS) were purchased from Aldrich Chemical Comaany. Bis(3-sulfonatophenyl)phenylphosphine disodium salt (TPPDS) was prepared by the published procedure (Kuntz, E., U.S. Pat. No. 4,248,802). (3-Sulfonatophenyl)diphenylphosphine monosodium salt (TPPMS)was purchased from TCI America, Inc. Tricine was obtained from Research Organics, Inc. Technetium-99m-pertechnetate (^(99m)TcO₄−) was obtained from a DuPont Pharma ⁹⁹Mo/^(99m)Tc Technelite® generator. In-111-chloride (Indichlor®) was obtained from Amersham Medi-Physics, Inc. Sm-153-chloride and Lutetium-177-chloride were obtained from the University of Missouri Research Reactor (MURR). Yttrium-90 chloride was obtained from the Pacific Northwest Research Laboratories. Dimethylformamide (DMF), ethyl acetate, chloroform (CHCl₃), methanol (MeOH), pyridine and hydrochloric acid (HCl) were obtained from Baker. Acetonitrile, dichloromethane (DCM), acetic acid (HOAc), trifluoroacetic acid (TFA), ethyl ether, triethylamine, acetone, and magnesium sulfate were commercially obtained. Absolute ethanol was obtained from Quantum Chemical Corporation.

Example 1

Synthesis of 2-(((4-(4-(((3-(2-(2-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic Acid

Part A—Preparation of N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)(phenylmethoxy)formamide

A solution of 4,7,10-trioxa-1,13-tridecanediamine (158 mL, 0.72 mol), TEA (16.7 mL, 0.12 mol), and MeOH (300 mL) in peroxide-free THF (1,000 mL) was placed in a 3 liter 3-neck flask fitted with a mechanical stirrer, a thermometer, and an addition funnel with nitrogen line. The addition funnel was charged with a solution of benzyl chloroformate (17.1 mL, 0.12 mol) in peroxide-free THF (1,000 mL). The contents of the flask were cooled below 5° C. The contents of the addition funnel were added to the flask with rapid stirring over 4 h while keeping the temperature below 5° C. The solution was stirred an additional 30 min and concentrated to give a thick syrup. This syrup was taken up in saturated NaCl (1800 mL) and 10% Na₂CO₃ (200 mL) and extracted with ether (3×1,000 mL). The combined ether extracts were washed with saturated NaCl (500 mL), dried (MgSO₄), and concentrated to give a pale yellow oil (36.74 g). Flash chromatography on a 7×29 cm silica gel column (DCM/MeOH/TEA, 20/15/0.5) gave the title compound as a colorless syrup (19.14 g, 45%). ¹H NMR (CDCl₃): 7.33-7.25 (m, 5H), 5.59 (s, 1H), 5.06 (s, 2H), 3.62-3.45 (m, 12H), 3.32-3.25 (m, 2H), 2.74 (t, J=6.7 Hz, 2H), 1.75 (pentet, J=6.0 Hz, 2H), 1.67 (pentet, J=6.4 Hz, 2H), 1.33 (s, 2H); MS: m/e 355.4 [M+H]; High Resolution MS: Calcd for C₁₈H₃₁N₂O₅ [M+H]: 355.2233, Found: 355.2222.

Part B—Preparation of Methyl 3-((tert-Butoxy)carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoate

Biphenyl-4,4′-disulfonyl chloride (2.64 g, 7.5 mmol, freshly recrystallized from CHCl₃) and DCM (200 mL) were placed in a 500 mL 3-neck flask fitted with a thermometer, an addition funnel, and a nitrogen line. The addition funnel was charged with a solution of N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)(phenylmethoxy)formamide (1.77 g, 5.0 mmol) and DIEA (0.87 mL, 5.0 mmol) in DCM (40 mL). The contents of the flask were cooled below 5° C. The contents of the addition funnel were added to the flask with rapid stirring over 3 h while keeping the temperature of the flask below 5° C. The addition funnel was charged with a solution of N-β-Boc-L-α,β,-diaminopropionic acid methyl ester hydrochloride (2.55 g, 10 mmol) and DIEA (3.8 mL, 22 mmol) in DCM (25 mL). This solution was added to the flask with stirring at 5° C. over 15 min, and stirred at ambient temperatures for an additional 20 h. The reaction solution was washed consecutively with 0.1 N HCl (100 mL) and water (2×100 mL), dried (MgSO₄), and concentrated to give a viscous oil (5.79 g). Flash chromatography on a 5×21 cm silica gel column (85/15 EtOAc/hexanes, followed by 100% EtOAc) gave a colorless amorphous solid.

Recrystallization from toluene (85 mL) gave the title compound as a colorless solid (2.52 g, 59%). MP: 104.5-106.5° C.; ¹H NMR (CDCl₃): 8.00-7.90 (m, 4H), 7.72-7.64 (m, 4H), 7.46-7.24 (m, 5H), 5.96-5.88 (m, 1H), 5.86-5.73 (m, 1H), 5.41 (s, 1H), 5.16-5.00 (m, 3H), 4.15-4.02 (m, 1H), 3.68-3.39 (m, 17H), 3.34-3.22 (m, 2H), 3.13-3.03 (m, 2H), 1.80-1.62 (m, 4H), 1.39 (s, 9H); ¹³C NMR (CDCl₃): 170.2, 156.5, 156.1, 143.9, 143.0, 140.4, 139.4, 136.7, 128.4, 128.1, 128.0, 127.9, 127.9, 127.8, 127.3, 80.1, 70.6, 70.5, 70.2, 70.1, 70.0, 69.6, 66.5, 56.1, 52.9, 43.2, 42.4, 39.3, 29.4, 28.5, 28.2; MS: m/e 868.3 [M+NH₄]; High Resolution MS: Calcd for C₃₉H₅₅N₄O₁₃S₂ [M+H]: 851.3207, Found: 851.3226.

Part C—Preparation of Methyl 2-(((4-(4-(((3-(2-(2-(3-((Phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((1-(3-((1-(triphenylmethyl)imidazole-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propanoate.

The product from Part B, above (141 mg, 0.166 mmol) was dissolved in 25/75 TFA/DCM (5 mL) and allowed to react at ambient temperatures for 15 min. The solution was concentrated to give a viscous amber oil. This oil was dissolved in anhydrous DMF (3 mL) and treated with TEA until basic to pH paper. In a separate flask, 1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxylic acid (76 mg, 0.141 mmol), TEA (0.059 mL, 0.422 mmol), and HBTU (63.9 mg, 0.169 mmol) were dissolved in anhydrous DMF (3 mL). The resulting solution was stirred at ambient temperatures for 5 min and combined with the DMF solution from the TFA deprotection. The solution was concentrated after 2 h to give a viscous amber oil. The oil was dissolved in EtOAc (175 mL) and washed consecutively with water (50 mL), saturated NaHCO₃ (25 mL), and saturated NaCl (50 mL). The combined aqueous washings were back-extracted with EtOAc (50 mL). The combined EtOAc layers were dried (MgSO₄) and concentrated to give a viscous amber oil. Purification by flash chromatography on a 2×16 cm silica gel column using a EtOAc/MeOH step gradient (95/5, 93/7, 85/15) gave the title compound as a pale yellow foamy solid (86 mg, 48%). MS: m/e 1273.4 [M+H]; High Resolution MS: Calcd for C₆₈H₇₃N₈O₁₃S₂ [M+H]: 1273.4738, Found: 1273.4730.

Part D—Preparation of 2-(((4-(4-(((3-(2-(2-(3-((Phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((1-(3-((1-(triphenylmethyl)imidazole-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic Acid

The product from Part C, above (200 mg, 0.159 mmol) was hydrolyzed in a mixture of peroxide-free THF (8.0 mL), 3 N LiOH (0.80 mL), and water (1.20 mL). The mixture was stirred at ambient temperatures under an atmosphere of nitrogen for 3 h. The THF was removed under reduced pressure and the resulting yellow solution was diluted with water (15 mL). The solution was adjusted to pH 5.0, and the resulting yellow ppt was extracted into DCM (4×25 mL). The combined DCM extracts were dried (MgSO₄), and concentrated to give the title compound as a yellow solid (174 mg, 88%). MS: m/e 1246.4 [M+H]; High Resolution MS: Calcd for C₆₆H₇₂N₉O₁₂S₂ [M+H]: 1246.4741, Found: 1246.4730.

Part E—Preparation of 2-(((4-(4-(((3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic Acid

The product from Part D, above (154 mg, 0.124 mmol) was dissolved in degassed TFA (15 mL) and triethylsilane (0.10 mL, 0.626 mmol), and heated at 70° C. under an atmosphere of nitrogen for 1.5 h. The solution was concentrated and the resulting oily solid was dissolved in water (75 mL) and washed with ether (2×20 mL). The combined ether washings were back-extracted with water (10 mL). The two aqueous solutions were combined, and lyophilized to give the title compound as a hygroscopic off-white solid, (140 mg). MS: m/e 870.3 [M+H]; High Resolution MS: Calcd for C₃₉H₅₂N₉O₁₀S₂ [M+H]: 870.3278, Found; 870.3301.

Part F—Preparation of 2-(((4-(4-(((3-(2-(2-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic Acid.

The product from Part E, above (15 mg, 0.0137 mmol) was dissolved in anhydrous DMF (2.5 mL) and treated with TEA until basic to pH paper. The solution was treated with 2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonic acid (9.0 mg, 0.020 mmol) and stirred at ambient temperatures under a nitrogen atmosphere for 24 h. The DMF was removed under vacuum, and the resulting oil was dissolved in 50% ACN and purified by preparative HPLC on a Vydac C-18 column (22×250 mm) using a 2.52%/min gradient of 0 to 63% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The main product peak eluting at 21.9 min was collected and lyophilized to give the title compound as a colorless powder (9.0 mg, 51%). MS: m/e 1173.4 [M+H]; High Resolution MS: Calcd for C₅₂H₆₁N₁₂O₁₄S₃ [M+H]: 1173.3592, Found: 1173.360.

Example 2

Synthesis of 2-(2-Aza-2-((5-(N-(1,3-bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propyl)carbamoyl)(2-pyridyl))amino)vinyl)benzenesulfonic Acid

Part A—Preparation of N,N′-Bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)-2-((tert-butoxy)carbonylamino)pentane-1,5-diamide

The product from Example 1, Part D (44 mg, 0.04 mmol) was dissolved in anhydrous DMF (5 mL) and made basic to pH paper with TEA. This solution was treated with the bis-N-hydroxysuccinimide ester of Boc-Glu-OH (7.9 mg, 0.018 mmol) and stirred at ambient temperatures under a nitrogen atmosphere for 18 h. The DMF was removed under vacuum and the resulting oil was dissolved in 50% ACN and purified by preparative HPLC on a Vydac C-18 column (22×250 mm) using a 2.1%/min gradient of 0 to 63% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The peak eluting at 21.1 min was collected and lyophilized to give the monomer 2-((tert-butoxy)carbonylamino)-4-(N-(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)butanoic acid as a colorless solid in 82% purity A second HPLC purification using the above method gave 100% pure monomer (3.4 mg, 7.0%). MS: m/e 1099.5 [M+H], 550.5 [M+2H].

The main peak eluting at 22.4 min was collected and lyophilized to give the title compound as a colorless solid (11 mg, 25%). MS: m/e 1952.1 [M+H]; 976.9 [M+2H]; 651.6 [M+3H]; High Resolution MS: Calcd for C₈₈H₁₁₆N₁₉O₂₄S₄: 1950.7323, Found: 1950.7340.

Part B—Preparation of 2-(2-Aza-2-((5-(N-(1,3-bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propyl)carbamoyl)(2-pyridyl))amino)vinyl)benzenesulfonic Acid

The dimeric product from Part A, above (11 mg. 0.0050 mmol) was dissolved in degassed TFA (2 mL) and stirred at ambient temperatures under a nitrogen atmosphere for 15 min and concentrated to a viscous amber oil. This oil was dissolved in anhydrous DMF (2 mL) and made basic with TEA. The solution was treated with 2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonic acid (0.024 mmol) and stirred at ambient temperatures under a nitrogen atmosphere for 56 h. The DMF was removed under vacuum, and the resulting oil was dissolved in 50% ACN and purified by preparative HPLC on a Vydac C-18 column (22×250 mm) using a 2.1%/min gradient of 0 to 63% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The main product peak eluting at 20.7 min was collected and lyophilized to give the title compound as a colorless powder (5 mg, 42%). MS: m/e 1077.6 [M+2H], 719.0 [M+3H]; High Resolution MS: Calcd for C₉₆H₁₁₇N₂₂O₂₆S₅: 2153.7112, Found: 2153.7140.

Example 3

Synthesis of 2-((6-((1-Aza-2-(sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)-4-(N-(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)butanoic Acid

The monomeric product from Example 2, Part A (3.4 mg, 0.0031 mmol) was dissolved in TFA (1.5 mL) and allowed to react for 15 min at ambient temperatures, and concentrated to a viscous amber oil. This oil was dissolved in anhydrous DMF (2 mL) and made basic to pH paper with TEA. This solution was treated with 2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonic acid (5.3 mg, 0.012 mmol) and stirred at ambient temperatures under a nitrogen atmosphere for 7 days. The DMF was removed under vacuum and the resulting oil was dissolved in 50% ACN and purified by preparative HPLC on a Vydac C-18 column (22×250 mm) using a 2.1%/min gradient of 0 to 63% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The main product peak eluting at 18.1 min was collected and lyophilized to give the title compound as a colorless powder (1.8 mg, 41%). MS: m/e 1302.5 [M+H], 651.9 [M+2H]; High Resolution MS: Calcd for C₅₇H₆₈N₁₃O₁₇S₃ [M+H]: 1302.4018, Found: 1302.4030.

Example 4

Synthesis of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic Acid Bis(trifluoroacetate) Salt

Part A—Phenylmethyl 2-(1,4,7,10-Tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetate

A solution of tert-butyl (1,4,7,10-tetraaza-4,7-bis (((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetate (0.922 g, 1.79 mmol), TEA (1.8 mL) and benzyl bromoacetate (0.86 mL, 5.37 mmol) in anhydrous DMF (24 mL) was stirred at ambient temperatures under a nitrogen atmosphere for 24 h. The DMF was removed under vacuum and the resulting oil was dissolved in EtOAc (300 mL). This solution was washed consecutively with water (2×50 mL) and saturated NaCl (50 mL), dried (MgSO₄), and concentrated to give the title compound as an amorphous solid (1.26 g). MS: m/e 663.5 [M+H].

Part B—2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetic acid

The product from Part A, above (165 mg, 0.25 mmol) was hydrogenolyzed over 10% Pd on carbon (50 mg) in EtOH (15 mL) at 60 psi for 24 h. The catalyst was removed by filtration through filter aid and washed with EtOH. The filtrates were concentrated to give the title compound as an amorphous solid (134 mg, 94%). MS: m/e 573.5 [M+H].

Part C—Preparation of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic Acid Pentakis(trifluoroacetate) Salt

A solution of 2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetic acid (55 mg, 0.06 mmol), DIEA (0.063 mL, 0.36 mmol), and HBTU (17 mg, 0.045 mmol) in anhydrous DMF (3 mL) was stirred under nitrogen at ambient temperatures for 15 min and treated with the product of Example 1, Part E. Stirring was continued 1 h and the DMF was removed under vacuum. The resulting amber oil was dissolved in 10% ACN and purified by preparative HPLC on a Vydac C-18 column (22×250 mm) using a 2.1%/min gradient pof 0 to 63% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The main product peak eluting at 23.0 min was collected and lyophilized to give the title compound as a colorless, hygroscopic solid (22 mg, 37%). MS: m/e 1424.8 [M+H]; 713.2 [M+2H].

Part D—Preparation of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic Acid Bis(trifluoroacetate) Salt

The product of Part C, above, (10 mg, 0.005 mmol) and triethylsilane (0.10 mL) were dissolved in degassed TFA (2.0 mL) and heated at 50° C. under nitrogen for 1 h. The solution was concentrated under vacuum and the resulting solid was dissolved in 7% ACN and purified by preparative HPLC on a Vydac C-18 column (22×250 mm) using a 1.5%/min gradient of 0 to 45% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The main product peak eluting at 19.3 min was collected and lyophilized to give the title compound as a colorless solid (3.0 mg, 40%). MS: m/e 1256.5 [M+H]; 629.0 [M+2H]; 419.9 [M+3H].

The analytical HPLC methods utilized for examples 5 and 6 are described below:

Instrument: HP1050

Column: Vydac C18(4.6×250 mm)

Detector: Diode array detector 220 nm/500 ref

Flow Rate: 1.0 mL/min.

Column Temp: 50° C.

Sample Size: 15 uL

Mobile Phase:

A: 0.1% TFA in water

B: 0.1% TFA in ACN/Water (9:1)

Method A Gradient: Time (min) % A % B 0 80 20 20 0 100 30 0 100 31 80 20 Method B Gradient: Time (min) % A % B 0 98 2 16 63.2 36.8 18 0 100 28 0 100 30 98 2

Example 5

Synthesis of 2-(6-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)hexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-propanoic acid

Part A. Preparation of Methyl 2-((phenylmethoxy)-carbonylamino-3-((1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propanoate

1-[3-[N-(-Triphenylmethylimidazo-2-yl)amino]propylyl]-5-carboxyindazole (0.950 g, 1.80 mmol), HBTU (0.751 g, 1.98 mmol), and methyl 3-amino-2(S)-(benzyloxycarbonylamino)propionate (0 624 g, 2.16 mmol) were dissolved in N,N-dimethylformamide (10 mL). Diisopropylethyl amine (94.1 μL, 5.40 mmol) was added and the reaction mixture was stirred under N₂ for 18 h. The reaction mixture was then concentrated to an oil under high vacuum. The oil was brought up in water. The water layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to a small volume. Product precipitated upon addition of hexane. The product was filtered, washed with hexane and dried under high vacuum to give 1.6128 g (117%) of product. ESMS: Calcd. for C₄₅H₄₃N₇O₅, 761.33; Found, 762.2 [M+H]+1. Analytical HPLC, Method A, R_(t)=17.00 min, Purity=90%

Part B. Preparation of 2-((Phenylmethoxy)carbonylamino-3-((1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid

Methyl 2-((phenylmethoxy)-carbonylamino-3-((1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propanoate (1.55 g, 2.03 mmol) was dissolved in tetrahydrofuran (20 mL). Lithium hydroxide monohydrate (1.71 g, 40.6 mmol) was dissolved in water and added to the reaction. The reaction was stirred overnight under N₂ for 18h. The tetrahydrofuran was removed under high vacuum. The pH of the remaining aqueous layer was adjusted to 5 with 1N HCl. The aqueous layer was extracted with methylene chloride. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to an oil under high vacuum. The oil was recrystallized from hexane:ethyl acetate to give 800.9 mgs (53%) of product. ESMS: Calcd. for C₄₄H₄₁N₇O₅, 747.32; Found, 748.3 [M+H]+1 Analytical HPLC, Method A, R_(t)=15.66 min, Purity=94%

Part C. Preparation of 2-Amino-3-((1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid

2-((Phenylmethoxy)carbonylamino-3-((1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (0.750 g, 1.00 mmol) was added to Pd/C (1.00 g) in ethanol (20 mL). The reaction was evacuated and purged with nitrogen twice. The reaction was then evacuated and purged with hydrogen twice, and then maintained under an atmosphere of hydrogen for 24 h. The reaction was filtered through celite. The filtrate was concentrated to an oil. The oil was recrystallized from hexane:ethyl acetate to give 215.6 mgs (35%) of product. ESMS: Calcd. for C₃₆H₃₅N₇O₃, 613.28; Found, 614.2 (M+H]+1 Analytical HPLC, Method A, R_(t)=12.26 min, Purity=90%

Part D. Preparation of 2-Amino-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid

2-Amino-3-((1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (0.203 g, 0.331 mmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction was refluxed for 1 h. The reaction was concentrated to an oil under high vacuum. The oil was triturated with ether. The product was filtered, washed with ether, dissolved in 50/50 acetonitrile/water, and lyophilized to give 171.0 mgs (106%) of product. ESMS: Calcd. for C₁₇H₂₁N₇O₃, 371.17; Found, 372.0 [M+H]+1 Analytical HPLC, Method B, R_(t)=9.48 min, Purity=95%

Part E. Preparation of 2-(6-((Tert-butoxy)carbonylamino)hexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid

2-Amino-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (0.050 g, 0.103 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (43.1 μL, 0.309 mmol) was added and the reaction was stirred for 5 minutes. A precipitate formed so methyl sulfoxide (1 mL) was added. Succinimidyl N-boc-6-aminohexanoate (0.0406 g, 0.124 mmol) was added and the reaction was stirred under N₂ for 18 h. The reaction was then concentrated to an oil under high vacuum. The oil was purified by the following method (Preparative HPLC Method A) to give 39.9 mgs (66%) of product. ESMS: Calcd. for C₂₈H₄₀N₈O₆, 584.31; Found, 585.2 [M+H]+1. Analytical HPLC, Method B, R_(t)=18.72 min, Purity=98%

Preparative HPLC Method A:

Instrument: Rainin Rabbit; Dynamax software

Column: Vyadac C-18 (21.2 mm×25 cm)

Detector: Knauer VWM

Flow Rate: 15 ml/min

Column Temp: RT

Mobile Phase:

A: 0.1% TFA in H₂O

B: 0.1%TFA in ACN/H₂O (9:1)

Gradient: Time (min) % A % B 0 98 2 16 63.2 36.8 18 0 100 28 0 100 30 98 2

Part F. Preparation of 2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid

2-(6-((Tert-butoxy)-carbonylamino)hexanoylamino)-3-((1-(3-(imidazol-2-ylamino)-propyl)(1H-indazol-5-yl))carbonylamino)-propanoic acid (0.0322 g, 0.0551 mmol) was dissolved in methylene chloride (1 mL). Trifluoroacetic acid (1 mL) was added, and the reaction was stirred for 2 h. The reaction was concentrated to an oil under high vacuum. The oil was triturated with ether. The product was filtered, washed with ether, dissolved in 50/50 acetonitrile/water, and lyophilized to give 29.9 mgs (91%) of product. ESMS: Calcd. for C₂₃H₃₂N₈O₄, 464.25; Found, 485.2 [M+H]+1 Analytical HPLC, Method B, R_(t)=111.02 min, Purity=97%

Part G. Preparation of 2-(6-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)-hexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid

2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)-propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (0.0265 g, 0.0443 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (18.5 μL, 0.133 mmol) was added, and the reaction was stirred for 5 min. 2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]-methyl]-benzenesulfonic acid, monosodium salt (0.0234 g, 0.0532 mmol) was added, and the reaction was stirred for 4 days. The reaction was concentrated to an oil under high vacuum. The oil was purified by Preparative HPLC Method A to give 33.7 mgs (97%) of product. HRMS: Calcd. for C₃₆H₄₁N₁₁O₈S+H, 788.2938; Found, 788.2955. Analytical HPLC, Method B, R_(t)=14.06 min, Purity=90%

Example 6

Synthesis of 2-((6-((1-Aza-2-(2-sulfophenyl)vinyl)-amino)(3-pyridyl))carbonylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid

2-Amino-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (0.025 g, 0.0515 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (21.5 μL, 0.154 mmol) was added, and the reaction was stirred for 5 min. 2-[[[5-[[(2,5-Dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]-methyl]-benzenesulfonic acid, monosodium salt (0.0272 g, 0.0515 mmol) was added, and the reaction was stirred under nitrogen for 18 h. The reaction mixture was concentrated to an oil under high vacuum. The oil was purified by preparative HPLC using Preparative HPLC Method A to give 14.6 mgs (42%) of the desired product. ESMS: Calcd. for C₃₀H₃₀N₁₀O₇S, 674.20; Found, 697.1 [M+Na]+1. Analytical HPLC, Method B, R_(t)=13.48 min, Purity=95%

Example 7

Synthesis of [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonic acid]-Glu(2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)

Part A. Preparation of Boc-Glu(OSu)-OSu

To a solution of Boc-Glu-OH (8.0 g, 32.25 mmol), N-hydroxysuccinimide (8.94 g, 77.64 mmol), and DMF (120 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (14.88 g, 77.64 mol). The reaction mixture was stirred at room temperature for 48 h. The mixture was concentrated under high vacuum and the residue was brought up in 0.1 N HCl and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, saturated sodium bicarbonate and then saturated sodium chloride, dried over MgSO₄, and filtered. The filtrate was concentrated in vacuo and purified via reverse-phase HPLC (Vydac C18 column, 18 to 90% acetonitrile gradient containing 0.1% TFA, R_(t)=9.413 min) to afford 8.5 g (60%) of the desired product as a white powder. ¹H NMR (CDCl₃): 2.98-2.70 (m, 11H), 2.65-2.25 (m, 2H), 1.55-1.40 (s, 9H); ESMS: Calculated for C₁₈H₂₃N₃O₁₀, 441.1383 Found 459.2 [M+NH₄]+1

Part B. Preparation of Glu{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid}{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid}

A solution of 2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (1 mmol), diisopropylethylamine (3 mmol), and Boc-Glu(OSu)OSu (0.5 mmol) is dissolved in DMF (50 mL). The reaction mixture is stirred under nitrogen and at room temperature for 18 h. The solvents are removed in vacuo and the crude material is triturated in ethyl acetate, filtered and washed with ethyl acetate. The crude product thus obtained is dissolved in 50 mL of 50% TFA/DCM and the reaction mixture is stirred for 3 h at room temperature under nitrogen. TFA and DCM is then removed in vacuo and the title compound isolated and purified by preparative RP-HPLC.

Part C. Preparation of [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonic acid]-Glu(2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)(2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)

Glu(2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)(2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid) (0.0481 mmol) is dissolved in DMF (2 mL). Triethylamine (20.1 μL, 0.144 mmol) is added, and after 5 min of stirring 2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]-methyl]-benzenesulfonic acid, monosodium salt (0.0254 g, 0.0577 mmol) is added. The reaction mixture is stirred for 20 h and then concentrated to an oil under high vacuum. The oil is purified by preparative RP-HPLC to obtain the desired product.

Example 8

Synthesis of [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonic acid]-Glu-bis-[Glu(2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)(2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)]

Part A. Preparation of Glu-Bis[Glu{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}]

A solution of Glu{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid}{2-(6-aminohexanoylamino)-3-1((1-i(3-(imidazol-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid}(1 mmol), disopropylethylamine (3 mmol), and Boc-Glu(OSu)OSu (0.5 mmol) is dissolved in DMF (50 mL). The reaction mixture is stirred under nitrogen and at room temperature for 18 h. The solvents are removed in vacuo and the crude material is triturated in ethyl acetate, filtered and washed with ethyl acetate. The crude product thus obtained is dissolved in 50 mL of 50% TFA/DCM and the reaction mixture is stirred for 3 h at room temperature under nitrogen. TFA and DCM is then removed in vacuo and the title compound isolated and purified by preparative RP-HPLC.

Part B: Preparation of [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonic acid]-Glu-bis-[Glu(2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)(2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)]

Glu-bis-[Glu{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid}{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid}] (0.0481 mmol) is dissolved in DMF (2 mL). Triethylamine (20.1 μL, 0.144 mmol) is added, and after 5 min of stirring 2-[[[5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl]hydrazono]-methyl]-benzenesulfonic acid, monosodium salt (0.0254 g, 0.0577 mmol) is added. The reaction mixture is stirred for 20 h and then concentrated to an oil under high vacuum. The oil is purified by preparative RP-HPLC to obtain the desired product.

Example 9

Synthesis of of 2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-l-cyclododecyl)acetyl-{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}

Part A. Preparation of 2-(1,4,7,10-tetraaza-4,7,10-tris(t-butoxycarbonylmethyl)-1-cyclododecyl)acetyl-{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}

To a solution of tris(t-butyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (28 mg, 0.049 mmol) and Hunig's base (14 μL) in DMF (2 mL) is added HBTU (17 mg, 0.0456 mmol) and the mixture is stirred for 5 min. To this is added a solution of 2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid (0.0326 mmol) in DMF (1 mL) and the reaction mixture is allowed to stir under nitrogen at room temperature for 4 h. The solvent is removed in vacuo and the residue is purified by preparative RP-HPLC to obtain the product as a lyophilized solid.

Part B. Preparation of 2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}

A solution of 2-(1,4,7,10-tetraaza-4,7,10-tris(t-butoxycarbonylmethyl)-1-cyclododecyl)acetyl-2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid (8.71 mmol) in TFA (3 mL) is stirred at room temperature under nitrogen for 5 h. The solution is concentrated in vacuo and the residue is purified by preparative RP-HPLC to obtain the desired product as the lyophilized solid.

Example 10

Synthesis of 2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-l-cyclododecyl)acetyl-Glu{2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}{2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}

Part A. Preparation of 2-(1,4,7,10-tetraaza-4,7,10-tris(t-butoxycarbonylmethyl)-1-cyclododecyl)acetyl-Glu{2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}{2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}

To a solution of tris(t-butyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (28 mg, 0.049 mmol) and Hunig's base (14 μL) in DMF (2 mL) is added HBTU (17 mg, 0.0456 mmol) and the mixture is stirred for 5 min. To this is added a solution of Glu{2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)(2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid} (0.0326 mmol) in DMF (1 mL) and the reaction mixture is allowed to stir under nitrogen at room temperature for 4 h. The solvent is removed in vacuo and the residue is purified by preparative RP-HPLC to obtain the product as a lyophilized solid.

Part B. Preparation of 2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-Glu{2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}{2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}.

A solution of 2-(1,4,7,10-tetraaza-4,7,10-tris(t-butoxycarbonylmethyl)-1-cyclododecyl)acetyl-Glu{2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid}{2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid} (8.71 mmol) in TFA (3 mL) is stirred at room temperature under nitrogen for 5 h. The solution is concentrated in vacuo and the residue is purified by preparative RP-HPLC to obtain the desired product as the lyophilized solid.

Example 11

Synthesis of DOTA/N,N′-Bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino) propoxy)ethoxy)ethoxy)propyl)-2-(amino)pentane-1,5-diamide Tris(trifluoroacetate) Salt Conjugate

Part A—Preparation of DOTA Tris-t-Butyl Ester/N,N′-Bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)-ethoxy)ethoxy)propyl)-2-(amino)pentane-1,5-diamide Hexakis(trifluoroacetate) Salt Conjugate

A solution of the product from Example 2, Part A in degassed TFA is allowed to stand at ambient temperatures under nitrogen for 15 min. The solution is concentrated and the resulting oil is dissolved in 50% ACN. The TFA salt is converted to the free base by treatment with an ion exchange resin such as Bio-Rad AG-3X4A, hydroxide form, until the pH of the solution is raised to 6.5. The resin is removed by filtration and the filtrate is lyophilized to give the free base of the deprotected dimer.

A solution of DOTA tris-t-butyl ester and DIEA in anhydrous DMF are treated with HBTU and allowed to react 15 min at ambient temperatures under nitrogen. The deprotected dimer from above is added to this solution and stirring is continued at ambient temperatures under nitrogen for 18 h. The DMF is removed under vacuum and the resulting oil is purified by preparative HPLC on a C18 column using a water:ACN:0.1% TFA gradient. The product fraction is lyophilized to give the title compound.

Part B—Preparation of DOTA/N,N′-Bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)-2-(amino)pentane-1,5-diamide Tris(trifluoroacetate) Salt Conjugate

The product of Part A, above, and Et₃SiH are dissolved in degassed TFA and heated at 50° C. under nitrogen for 1 h. The solution is concentrated and the resulting residue is purified by preparative HPLC on a C18 column using a water:ACN:0.1% TFA gradient. The product fraction is lyophilized to give the title compound.

Example 12

Synthesis of DOTA/2-Amino-4-(N-(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)butanoic Acid Bis(trifluoroacetate) Salt

The title compound is prepared by the procedure described for Example 11 by substituting the monomeric product of Example 2, Part A for the dimeric product of Example 2, Part A.

Example 13

Synthesis of DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Bis(trifluoroacetate) Salt Conjugate

Part A—Ethyl 4-(3,5-Dimethylphenoxy)butanoate

Sodium metal (17.12 g, 0.744 mol) was added to anhydrous EtOH (350 mL) and stirred until dissolved. 3,5-Dimethylphenol was added and the solution was stirred 15 min at ambient temperatures. Ethyl 4-bromoacetate (58.7 mL, 0.41 mol) was added and the solution was stirred at ambient temperatures under a nitrogen atmosphere for 28 h. The EtOH was removed under vacuum and the oily solid was partitioned between water (1 L) and EtOAc (500 mL). The aqueous layer was extracted with additional EtOAc (500 mL). The combined EtOAc extracts were washed consecutively with saturated NaHCO₃ (300 mL) and saturated NaCl (300 mL), dried (MgSO₄), and concentrated to give an amber liquid. This liquid was vacuum fractional distilled through a 15 cm Vigreux column. The main fraction was collected from 91-117° C./6 mm Hg to gave the title compound as a colorless liquid (77.77 g, 89%). ¹H NMR (CDCl₃): 6.59 (s, 1H), 6.52 (s, 2H), 4.16 (q, J-7.16 Hz, 2H), 3.98 (t, J=6.14 Hz, 2H), 2.49 (t, J=7.34 Hz, 2H), 2.28 (s, 6H), 2.11-2.07 (m, 2H), 1.26 (t, J=7.16 Hz, 3H); Anal. calcd for C₁₄H₂₀O₃: C,71.16; H, 8.53, Found: C, 71.35; H, 8.59.

Part B—4-(3,5-Dimethylphenoxy)butanoic Acid

The product of part A, above (75.52 g, 0.320 mol) and KOH pellets (38.5 g, 0.584 mol) were dissolved in absolute EtOH (1.50 L) and heated at reflux for 3 h. The solution was concentrated to a colorless solid, which was taken up in water (2.0 L) and washed with ether (2×750 mL). The aqueous layer was adjusted to pH 1 with concd HCl (55 mL) and the resulting oily ppt was extracted into EtOAc (2×500 mL). The combined EtOAc extracts were washed consecutively with water (300 mL) and saturated NaCl, dried (MgSO₄), and concentrated to give a colorless solid (64.13 g). Recrystallization from hexanes (500 mL) gave the title compound as a colorless solid (59.51 g, 89%). MP: 66-68.5° C.; ¹H NMR (CDCl₃): 11.70 (bs, 1H), 6.59 (s, 1H), 6.52 (s, 2H), 3.99 (t, J=6.06 Hz, 2H), 2.57 (t, J=7.29 Hz, 2H), 2.28 (s, 6H), 2.12-2.08 (m, 2H); Anal. calcd for C₁₂H₁₆O₃: C, 69.21; H, 7.74, Found: C, 69.23; H, 7.40.

Part C—4-(4-(Chlorosulfonyl)-3.5-dimethylphenoxy)butanoic Acid

A solution of the product of Part B, above (20.8 g, 0.100 mol) in CHCl₃ (100 mL) was cooled to 0° C. and treated with chlorosulfonic acid (36 mL, 0.54 mol) dropwise and with rapid stirring while keeping the temperature of the reaction at 0° C. The resulting gelatinous mixture was stirred an additional 10 min and poured onto an ice/water mixture (600 mL). The resulting solid ppt was collected by filtration, washed with water (3×75 mL), and dried under vacuum to give a colorless solid (12.52 g). MP: 114-115° C. (with decomp); ¹H NMR (CDCl₃): 13.84 (bs, 1H), 6.50 (s, 2H), 3.91 (t, J=6.48 Hz, 2H), 2.48 (s, 6H), 2.32 (t, J=7.32 Hz, 2H), 1.89-1.84 (m, 2H); IR (KBr cm⁻¹): 1705 (s), 1370 (s), 1175 (s); MS: m/e 305.1 [M−H].

Part D—4-(4-(((2-((tert-Butoxy)carbonylamino)-1-(methoxycarbonyl)ethyl)amino)sulfonyl)-3,5-dimethylphenoxy) butanoic Acid

A solution of N-β-Boc-L-αβ, -diaminopropionic acid methyl ester hydrochloride (568 mg, 2.10 nmol) and DIEA (0.73 mL, 4.2 mmol) in DCM (5 mL) was cooled to 0° C. and treated with a suspension of the product of Part C, above (656 mg, 2.10 mmol) in DCM (20 mL) in small portions over a 15 min period. The reaction was stirred at ambient temperatures under a nitrogen atmosphere for 18 h. The reaction was diluted with DCM (100 mL) and washed with water (3×75 mL). The organic phase was dried (MgSO₄), and concentrated to give crude product (698 mg), which was purified by preparative HPLC on a Vydac C-18 column (50×250 m) using a 0.96%/min gradient of 18 to 58.5% ACN containing 0.1% TFA at a flow rate of 80 mL/min. The main product fraction eluting at 23.8 min was collected adjusted to pH 3, partially concentrated to remove ACN, and extracted with DCM (2×100 mL). The DCM extracts were dried (MgSO₄) and concentrated to give the title compound as a colorless solid (297 mg, 29%). ¹H NMR (CDCl₃): δ6.61 (s, 2H), 5.66 (d, J=7.2 Hz, 1H), 4.90 (s, 1H), 4.03 (bs, 2H), 3.86 (bs, 1H), 3.59 (s, 3H), 3.49 (bs, 2H), 2.62 (s, 6H), 2.58-2.51 (m, 2H), 2.18-2.07 (m, 2H), 1.41 (s, 9H); MS: m/e 489.4 [M+H]; High Resolution MS: Calcd for C₂₁H₃₃N₂O₉S [M+Na]: 511.1726, Found: 511.1747; Anal. calcd for C₂₁H₃₂N₂O₉S: C, 51.62; H. 6.61; N, 5.74, Found: C, 51.47; H, 6.27; N, 5.48.

Part E—Methyl 3-((tert-Butoxy)carbonylamino)-2-(((2,6-dimethyl-4-(3-(N-(3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)phenyl)sulfonyl)amino)propanoate

A solution of the product from Part D, above (233 mg, 0.477 mmol), the product of Example 1, Part A (190 mg, 0.536 mmol), TEA (0.2 mL, 1.43 mmol), and HBTU (226 mg, 0.701 mmol) in anhydrous DMF (8 mL) was stirred at ambient temperatures under a nitrogen atmosphere for 1 h. The DMF was removed under vacuum and the oily residue was taken up in EtOAc (50 mL) and washed consecutively with 0.1 N HCl (35 mL), water (35 mL), and saturated NaCl (35 mL), dried (MgSO₄), and concentrated to give crude product as a yellow viscous oil. Flash chromatography on a 3×18 cm silica gel column (EtOAc/MeOH, 95/5) gave the title compound as a colorless viscous oil (393 mg, 100%). ¹H NMR (CDCl₃): δ7.34-7.28 (m, 5H), 6.60 (s, 2H), 6.26 (bs, 1H), 5.67 (bs, 1H), 5.29 (bs, 1H), 5.08 (s, 2H), 4.88 (bs, 1H), 3.99 (t, J=6.1 Hz, 2H), 3.88-3.84 (m, 1H), 3.62-3.40 (m, 17H), 3.37-3.26 (m, 4H), 2.62 (s, 6H), 2.32 (t, J=7.2 Hz, 2H), 2.08 (t, J=6.3 Hz, 2H), 1.79-1.70 (m, 4H), 1.41 (s, 9H); MS: m/e 825.5 [M+H]; High Resolution MS: Calcd for C₃₉H₆₁N₄O₁₃S [M+H]: 825.3955, Found: 825.3940.

Part F—Methyl 3-Amino-2-(((2,6-dimethyl-4-(3-(N-(3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)phenyl)sulfonyl)amino)propanoate

The product of Part E, above (750 mg, 0.91 mmol) was dissolved in 4 M HCl/dioxane (25 mL) and stirred at ambient temperatures for 1 h. The solution was diluted with ether (500 mL) and the resulting gummy ppt was triturated with fresh ether (2×250 mL). The gummy solid was dissolved in water (100 mL) and adjusted to pH 9 with NaHCO₃, causing an oily ppt to form. This ppt was extracted into DCM (2×75 mL). The DCM extracts were dried (MgSO₄) and concentrated to give the title compound as a colorless oil (386 mg, 56%). MS: m/e 725.5 [M+H].

Part G—Preparation of Methyl 2-(((2,6-Dimethyl-4-(3-(N-(3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)phenyl)sulfonyl)amino)-3-((1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propionate

A solution of 1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxylic acid, methyl 3-amino-2-(((2,6-dimethyl-4-(3-(N-(3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)phenyl)sulfonyl)amino)propanoate, DIEA, and HBTU in anhydrous DMF are stirred at ambient temperatures under nitrogen for 4 h. The DMF is removed under vacuum and the resulting residue is dissolved in EtOAc and washed with water, saturated NaHCO3, and saturated NaCl. The EtOAc layer is dried (MgSO₄) and concentrated to dryness. The crude product is purified by flash chromatography on silica gel using EtOAc/MeOH.

Part H—Preparation of 2-(((4-(3-(N-(3-(2-(2-(3-(2-((tert-Butoxy)carbonylamino)-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Trifluoroacetate Salt

The product from Part G, above is hydrolyzed in a mixture of peroxide-free THF, water, and 3 N LiOH at ambient temperatures under nitrogen for 6 h. The THF is removed under vacuum and the resulting mixture is diluted with water and adjusted to pH 3 using 0.1 N HCl. The mixture is extracted with EtOAc, and the combined extracts are dried (MgSO₄) and concentrated.

A solution of the hydrolysis product from above and Et₃SiH in degassed TFA is heated at 70° C. under nitrogen for 1 h. The solution is concentrated and the resulting residue is dissolved in 50% ACN. The TFA salt is converted to the free base by treatment with an ion exchange resin such as Bio-Rad AG-3X4A, hydroxide form, until the pH of the solution is raised to 6.5. The resin is removed by filtration and the filtrate is lyophilized to give the free base.

The above material is dissolved in anhydrous DMF, and treated with the N-hydroxysuccinimide ester of Boc-cysteic acid (as described in Liebigs Ann. Chem. 1979, 776-783) and DIEA. The solution is stirred at ambient temperatures under nitrogen for 18 h, and the DMF is removed under vacuum. The resulting residue is purified by preparative HPLC on a C18 column using a water:ACN:0.1% TFA gradient. The product fraction is lyophilized to give the title compound.

Part I—Preparation of DOTA Tri-t-butyl Ester/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Pentakis(trifluoroacetate) Salt Conjugate

The product of Part H, above is dissolved in degassed TFA and stirred at ambient temperatures for 15 min. The solution is concentrated under vacuum, and the resulting residue is dissolved in 50% ACN and lyophilized to remove the last traces of TFA.

In a separate flask, a solution of DOTA tris-t-butyl ester and DIEA in anhydrous DMF are treated with HBTU and allowed to react 15 min at ambient temperatures under nitrogen. The deprotected product from above is added to this solution and stirring is continued at ambient temperatures under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is purified by preparative HPLC on a C18 column using a water:ACN:0.1% TFA gradient. The product fraction is lyophilized to give the title compound.

Part J—Preparation of DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Bis(trifluoroacetate) Salt Conjugate

The product of Part I, above, and Et₃SiH are dissolved in degassed TFA and heated at 50° C. under nitrogen for 1 h. The solution is concentrated and the resulting residue is purified by preparative HPLC on a C18 column using a water:ACN:0.I% TFA gradient. The product fraction is lyophilized to give the title compound.

Example 14

Synthesis of DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-(4-(phosphonooxy)phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Trifluoroacetate Salt Conjugate

The title compound is prepared by the procedure described for Example 13 by substituting Boc-Tyr(PO₃H₂)-OSu for Boc-Cys(O₃H)-OSu.

Example 15

Synthesis of DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-(4-(sulfooxy)phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Trifluoroacetate Salt Conjugate

The title compound is prepared by the procedure described for Example 13 by substituting Boc-Tyr(SO₃H)-OSu for Boc-Cys(O₃H)-OSu.

Example 16

Synthesis of DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-(ethyl-3,6-O-disulfo-β-D-galactopyranosyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Conjugate

Part A—Preparation of Boc-Glu(aminoethyl-3,6-O-disulfo-β-D-galactopyranosyl)-OSu

A solution of Boc-Glu-OMe, aminoethyl-3,6-O-disulfo-β-D-galactopyranoside (as described in Tet. Lett. 1997, 53, 11937-11952), DIEA, and HBTU in anhydrous DMEF is stirred at ambient temperatures under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is hydrolyzed using aqueous NaOH. The reaction solution is adjusted to pH 7 and purified by preparative anion exchange chromatography using a resin such as DEAE Cellulose and a Et₃NH₂CO₃ gradient. The product fraction is treated with a cation exchange resin, sodium form, to give the intermediate carboxylic acid as the sodium salt.

The above compound, N-hydroxysuccinimide, and DCC are dissolved in anhydrous DMF and stirred at ambient temperatures under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is purified by preparative anion exchange chromatography as above to give the title compound as the triethylammonium salt.

Part B—Preparation of DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-(ethyl-3,6-O-disulfo-β-D-galactopyranosyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Conjugate

The title compound is prepared by the procedure described for Example 13 by substituting Boc-Glu(aminoethyl-3,6-O-disulfo-β-D-galactopyranosyl)-OSu for Boc-Cys(O₃H)-OSu.

Example 17

Synthesis of DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-(6-deoxy-β-cyclodextryl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1 H-indazol-5-yl))carbonylamino)propionic Acid Bis(trifluoroacetate) Conjugate

Part A—Preparation of Boc-Glu(6-amino-6-deoxy-β-cyclodextryl)-OMe

A solution of Boc-Glu-OMe, 6-amino-6-deoxy-β-cyclodextrin (as described in J. Org. Chem. 1996, 61, 903-908), DIEA, and HBTU in anhydrous DMF is stirred at ambient temperatures under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is purified by preparative HPLC on a C18 column using a water:ACN:0.1% TFA gradient. The product fraction is lyophilized to give the title compound.

Part B—Preparation of Boc-Glu(6-amino-6-deoxy-β-cyclodextryl)-OSu

The product of Part A, above, is hydrolyzed by stirring in a mixture of LiOH, THF, and water at ambient temperatures under nitrogen for 4 h. The THF is removed under vacuum and the resulting mixture is diluted with water and adjusted to pH 3 using 0.1 N HCl. The mixture is extracted with EtOAc, and the combined extracts are dried (MgSO4) and concentrated. The resulting material is dissolved in anhydrous DMF along with N-hydroxysuccinimide, and DCC, and stirred at ambient temperatures under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is purified by preparative HPLC on a C18 column using a water:ACN:0.1% TFA gradient. The product fraction is lyophilized to give the title compound.

Part C—Preparation of DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-(6-deoxy-β-cyclodextryl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Bis(trifluoroacetate) Conjugate

The title compound is prepared by the procedure described for Example 13 by substituting Boc-Glu(6-amino-6-deoxy-β-cyclodextryl)-OSu for Boc-Cys(O₃H)-OSu.

Example 18

Synthesis of DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-(ω-methoxypolyethylene(5,000)glycoxyethyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Bis(trifluoroacetate) Conjugate

Part A—Preparation of Boc-Glu(amino-ω-methoxypolyethylene glycol)-OMe

A solution of Boc-Glu-OMe, amino-ω-methoxypolyethylene glycol, (MW=5,000), DIEA, and HBTU in anhydrous DMF is stirred at ambient temperatures under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is purified by preparative HPLC on a C18 column using a water:ACN:0.1% TFA gradient. The product fraction is lyophilized to give the title compound.

Part B—Preparation of Boc-Glu(amino-ω-methoxypolyethylene glycol)-OSu

The product of Part A, above, is hydrolyzed by stirring in a mixture of LiOH, THF, and water at ambient temperatures under nitrogen for 4 h. The THF is removed under vacuum and the resulting solution is adjusted to pH 7 using 0.1 N HCl. The solution is desalted using a Sephadex PD-10 desalting column and the product eluant is lyophilized. The resulting material is dissolved in anhydrous DMF along with N-hydroxysuccinimide, and DCC, and stirred at ambient temperatures under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is purified by preparative HPLC on a C18 column using a water:ACN:0.1% TFA gradient. The product fraction is lyophilized to give the title compound.

Part C—Preparation of DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-((ω-methoxypolyethylene(5,000)glycoxyethyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Bis(trifluoroacetate) Salt Conjugate

The title compound is prepared by the procedure described for Example 13 by substituting Boc-Glu(amino-ω-methoxypolyethylene glycol)-OSu for Boc-Cys(O₃H)-OSu.

Example 19

Synthesis of 2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-Tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-aminohexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Tris(trifluoroacetate) Salt

The title compound is prepared by the procedure described for Example 13 by substituting Boc-Lys(Cbz)-OSu for Boc-Cys(O₃H)-OSu.

Example 20

Synthesis of the DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-6-(2-(bis(phosphonomethyl)amino)acetylamino)hexanolylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic Acid Trifluoroacetate Salt Conjugate

A solution of bis(phosphonomethyl)glycine, DIEA, and HBTU in anhydrous DMF is stirred at ambient temperatures under nitrogen for 15 min, and treated with the product of Example 19. Stirring is continued for 18 h and the DMF is removed under vacuum. The resulting residue is purified by ion exchange chromatography.

Example 21

Synthesis of DTPA adduct of 2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid

To a solution of DTPA dianhydride (3 mmol), triethylamine (3 mmol) in DMF 20 mL is added a solution of 2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid (1 mmol) in DMF 5 mL dropwise. The reaction mixture is stirred for 18 h at room temperature under nitrogen, the volatiles are removed and the title compound is obtained after purification and isolation using preparative RP-HPLC.

The following procedure describe the synthesis of radiopharmaceuticals of the present invention of the formula ^(99m)Tc(VnA) (tricine)(phosphine), in which (VnA) represents a vitronectin receptor antagonist compound of the present invention bonded to the Tc through a diazenido (-N═N—) or hydrazido (═N—NH—) moiety. The diazenido or hydrazido moiety results from the reaction of the hydrazinonicotinamido group, present either as the free hydrazine or protected as a hydrazone, with the Tc-99m. The other two ligands in the Tc coordination sphere are tricine and a phosphine.

Examples 22-26

Synthesis of Complexes [^(99m)Tc(HYNIC-VnA) (tricine)(TPPTS)].

To a lyophilized vial containing 4.84 mg TPPTS, 6.3 mg tricine, 40 mg mannitol, succinic acid buffer, pH 4.8, and 0.1% Pluronic F-64 surfactant, was added 1.1 mL sterile water for injection, 0.2 mL (20 μg) of the appropriate HYNIC-conjugated vitronectin antagonist (VnA) in deionized water or 50% aqueous ethanol, and 0.2 mL of ^(99m)TcO₄—(50±5 mCi) in saline. The reconstituted kit was heated in a 100° C. water bath for 15 minutes, and was allowed to cool 10 minutes at room temperature. A sample of the reaction mixture was analyzed by HPLC. The RCP results are listed in the table 1.

TABLE 1 Analytical and Yield Data for ^(99m)Tc (VnA) (tricine) (TPPTS) Complexes Ret. Time Example No. Reagent No. (min) % Yield 22 1 18.6* 50 23 2 13.2** 55 24 3 17.0** 71 25 5 10.3*** 72 26 6 7.2* 64 *The HPLC method using a reverse phase C₁₈ Zorbax column (4.6 mm × 25 cm, 80 Å pore size) at a flow rate of 1.0 mL/min with a gradient mobile phase from 100% A (10 mM pH 6.0 phosphate buffer) to 75% B (acetonitrile) at 20 min. **The HPLC method using a reverse phase C₁₈ Zorbax column (4.6 mm × 25 cm, 80 Å pore size) at a flow rate of 1.0 mL/min with a gradient mobile phase from 100% A (10 mM pH 6.0 phosphate buffer) to 50% B (acetonitrile) at 20 min. ***The HPLC method using a reverse phase C₁₈ Zorbax column (4.6 mm × 25 cm, 80 Å pore size) at a flow rate of 1.0 mL/min with a gradient mobile phase from 100% A (10 mM pH 6.0 phosphate buffer) to 25% B (acetonitrile) at 20 min.

Example 27

Synthesis of the ¹⁷⁷Lu Complex of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic Acid

To a clean sealed 5 mL vial was added 0.5 mL of a solution of the conjugate of Example 4 (200 μg/mL in 0.5 M ammonium acetate buffer, pH 6.9), followed by 0.05 mL of gentisic acid (sodium salt, 10 mg/mL in 0.5 M ammonium acetate buffer, pH 6.9) solution, 0.3 mL of 0.25 M ammonium acetate buffer (pH 7.0), and 0.010 mL of 177LuC13 solution (1000 mCi/mL) in 0.05 N HCl. The resulting mixture was heated at 100° C. for 30 min. After cooling to room temperature, a sample of the resulting solution was analyzed by radio-HPLC and ITLC. The radiolabeling yield was 80%, and the retention time was 18.0 min.

HPLC Method

Column: Zorbax C18 , 25 cm×4.6 mm

Flow rate: 1.0 mL/min

Solvent A: 25 mM sodium phosphate buffer, pH 6.0

Solvent B: 100% CH3CN

t (min)  0 20 21 25 26 32 % Solvent B 15 20 60 60 15 15

The instant thin layer chromatography (ITLC) method used Gelman Sciences silica-gel strips and a 1:1 mixture of acetone and saline as eluant.

Example 28

Synthesis of the ⁹⁰Y Complex of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic Acid

To a clean sealed 5 mL vial was added 0.5 mL of a solution of the conjugate of Example 4 (200 μg/mL in 0.5 M ammonium acetate buffer, pH 6.9), followed by 0.05 mL of gentisic acid (sodium salt, 10 mg/mL in 0.5 M ammonium acetate buffer, pH 6.9) solution, 0.3 mL of 0.25 M ammonium acetate buffer (pH 7.0), and 0.010 mL of 90YCl3 solution (1000 mCi/mL) in 0.05 N HCl. The resulting mixture was heated at 100 C. for 30 min. After cooling to room temperature, a sample of the resulting solution was analyzed by radio-HPLC and ITLC. The radiolabeling yield was 85%, and the retention time was 18.2 min.

HPLC Method

Column: Zorbax C18 , 25 cm×4.6 mm

Flow rate: 1.0 mL/min

Solvent A: 25 mM sodium phosphate buffer, pH 6.0

Solvent B: 100% CH3CN

t (min)  0 20 21 25 26 32 % Solvent B 15 20 60 60 15 15

The instant thin layer chromatography (ITLC) method used Gelman Sciences silica-gel strips and a 1:1 mixture of acetone and saline as eluant.

Example 29

Synthesis of the ¹¹¹In Complex of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic Acid

To a lead shielded and closed autosampler vial was added: 80 μg of the conjugate of Example 4 dissolved in 160 μL 0.4 M ammonium acetate at pH 4.7 and 3 mCi In-111-chloride in 12.5 μL 0.05 N HCl. The solution was heated at 100° C. for 35-40 minutes. After cooling to room temperature, a sample of the resulting solution was analyzed by radio-HPLC and ITLC. The radiolabeling yield was 95%, and the retention time was 9.5 min.

HPLC Method

Column: Zorbax C18 , 25 cm×4.6 mm

Flow rate: 1.0 mL/min

Solvent A: 25 mM sodium phosphate buffer, pH 6.0

Solvent B: 100% CH3CN

t (min)  0 25 26 30 31 37 % Solvent B 16 18 60 60 16 16

The instant thin layer chromatography (ITLC) method used Gelman Sciences silica-gel strips and a 1:1 mixture of acetone and saline as eluant.

Example 30

Synthesis of the Gd Complex of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic Acid

The gadolinium complex of the conjugate of Example 4 is prepared according to the following procedure. 3-3.5 mg of the conjugate is dissolved in 2 mL 1 M ammonium acetate buffer at pH 7.0 , and one equivalent Gd(NO₃)₃ solution (0.02 M in water) is added to it. The reaction mixture is heated at 100 C. for 30 minutes and the product is isolated by preparative HPLC. The fraction containing the complex is lyophilized. The identity of the complex is confirmed by mass spectroscopy.

The following examples describe the synthesis of ultrasound contrast agents of the present invention.

Example 31

Part A Synthesis of 1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid)-dodecane-1,12-dione

A solution of disuccinimidyl dodecane-1,12-dioate (0.424 g, 1 mmol), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (1.489 g, 1 mmol) and 2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid TFA salt (1 mmol) in 25 ml chloroform is stirred for 5 min. Sodium carbonate (I mmol) and sodium sulfate (1 mmol) are added and the solution is stirred at room temperature under nitrogen for 18 h. DMF is removed in Vacuo and the crude product is purified to obtain the title compound.

Part B Preparation of Contrast Agent Composition

The 1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)-dodecane-1,12-dione is admixed with three other lipids, 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, and N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine in relative amounts of 1 wt. %:6 wt. %:54 wt. %:41 wt. %. An aqueous solution of this lipid admixture (1 mg/mL), sodium chloride (7 mg/mL), glycerin (0.1 mL/mL), propylene glycol (0.1 mL/mL), at pH 6-7 is then prepared in a 2 cc glass vial. The air in the vial is evacuated and replaced with perfluoropropane and the vial is sealed. The ultrasound contrast agent composition is completed by agitating the sealed vial in a dental amalgamator for 30-45 sec. to form a milky white solution.

Example 32

Part A. Preparation of Preparation of (ω-amino-PEG₃₄₀₀-α-carbonyl)-2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid

To a solution of N-Boc-ω-amino-PEG₃₄₀₀-α-carboxylate sucinimidyl ester (1 mmol) and 2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid (1 mmol) in DMF (25 mL) is added triethylamine (3 mmol). The reaction mixture is stirred under nitrogen at room temperature overnight and the solvent is removed in vacuo. The crude product is dissolved in 50% trifluoroacetic acid/dichloromethane and is stirred for 4 h. The volatiles are removed and the title compound is isolated as the TFA salt via trituration in diethyl ether.

Part B. Preparation of 1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-((ω)-amino-PEG₃₄₀₀-α-carbonyl)-(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid))-dodecane-1,12-dione

A solution of disuccinimidyl dodecane-1,12-dioate (1 mmol), 1,2-dipalmitoyl-sn-glycero-3-phosphpethanolamine (1 mmol) and (ω-amino-PEG₃₄₀₀-α-carbonyl)-cyclo(Arg-Gly-Asp-D-Phe-Lys) TFA salt (1 mmol) in 25 ml chloroform is stirred for 5 min. Sodium carbonate (1 mmol) and sodium sulfate (1 mmol) are added and the solution is stirred at room temperature under nitrogen for 18 h. DMF is removed in vacuo and the crude product is purified to obtain the title compound.

Part C Preparation of Contrast Agent Composition

The 1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-((ω-amino-PEG₃₄₀₀-α-carbonyl)-(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid))-dodecane-1,12-dione is admixed with three other lipids, 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, and N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine in relative amounts of 1 wt. %:6 wt. %:54 wt. %:41 wt. %. An aqueous solution of this lipid admixture (1 mg/mL), sodium chloride (7 mg/mL), glycerin (0.1 mL/mL), propylene glycol (0.1 mL/mL), at pH 6-7 is then prepared in a 2 cc glass vial. The air in the vial is evacuated and replaced with perfluoropropane and the vial is sealed. The ultrasound contrast agent composition is completed by agitating the sealed vial in a dental amalgamator for 30-45 sec. to form a milky white solution.

Example 33

Part A. Preparation of (ω-amino-PEG₃₄₀₀-α-carbonyl)-Glu-(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)₂

To a solution of N-BOC-ω-amino-PEG₃₄₀₀-α-carboxylate sucinimidyl ester (1 mmol) and Glu-(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)₂ (1 mmol) in DMF (25 mL) is added triethylamine (3 mmol). The reaction mixture is stirred under nitrogen at room temperature overnight and the solvent is removed in vacuo. The crude product is dissolved in 50% trifluoroacetic acid/dichloromethane and is stirred for 4 h. The volatiles are removed and the title compound is isolated as the TFA salt via trituration in diethyl ether.

Part B. Preparation of 1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-((ω-amino-PEG₃₄₀₀-α-carbonyl)-(Glu-(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)2))-dodecane-1,12-dione

A solution of disuccinimidyl dodecane-1,12-dioate (1 mmol), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine or DPPE (1 mmol) and (ω-amino-PEG₃₄₀₀-α-carbonyl)-Glu-(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)₂ TFA salt (1 mmol) in 25 ml chloroform is stirred for 5 min. Sodium carbonate (1 mmol) and sodium sulfate (1 mmol) are added and the solution is stirred at room temperature under nitrogen for 18 h. DMF is removed in vacuo and the crude product is purified to obtain the title compound.

Part C Preparation of Contrast Agent Composition

The 1-(1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamino)-12-((ω-amino-PEG₃₄₀₀-α-carbonyl)-(Glu-(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)₂))-dodecane-1,12-dione is admixed with three other lipids, 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, and N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine in relative amounts of 1 wt. %:6 wt. %:54 wt. %:41 wt. %. An aqueous solution of this lipid admixture (1 mg/mL), sodium chloride (7 mg/mL), glycerin (0.1 mL/mL), propylene glycol (0.1 mL/mL), at pH 6-7 is then prepared in a 2 cc glass vial. The air in the vial is evacuated and replaced with perfluoropropane and the vial is sealed. The ultrasound contrast agent composition is completed by agitating the sealed vial in a dental amalgamator for 30-45 sec. to form a milky white solution.

UTILITY

The pharmaceuticals of the present invention are useful for imaging angiogenic tumor vasculature in a patient or for treating cancer in a patient. The radiopharmaceuticals of the present invention comprised of a gamma emitting isotope are useful for imaging of pathological processes involving angiogenic neovasculature, including cancer, diabetic retinopathy, macular degeneration, restenosis of blood vessels after angioplasty, and wound healing. The radiopharmaceuticals of the present invention comprised of a beta, alpha or Auger electron emitting isotope are useful for treatment of pathological processes involving angiogenic neovasculature, by delivering a cytotoxic dose of radiation to the locus of the angiogenic neovasculature. The treatment of cancer is affected by the systemic administration of the radiopharmaceuticals resulting in a cytotoxic radiation dose to tumors.

The compounds of the present invention comprised of one or more paramagnetic metal ions selected from gadolinium, dysprosium, iron, and manganese, are useful as contrast agents for magnetic resonance imaging (MRI) of pathological processes involving angiogenic neovasculature.

The compounds of the present invention comprised of one or more heavy atoms with atmic number of 20 or greater are useful as X-ray contrast agents for X-ray imaging of pathological processes involving angiogenic neovasculature.

The compounds of the present invention comprised of an echogenic gas containing surfactant microsphere are useful as ultrasound contrast agents for sonography of pathological processes involving angiogenic neovasculature.

Representative compounds of the present invention were tested in the following in vitro assays and in vivo models and were found to be active.

Immobilized Human Placental avb3 Receptor Assay

The assay conditions were developed and validated using [I-125]vitronectin. Assay validation included Scatchard format analysis (n=3) where receptor number (Bmax) and Kd (affinity) were determined. Assay format is such that compounds are preliminarily screened at 10 and 100 nM final concentrations prior to IC50 determination. Three standards (vitronectin, anti-avB3 antibody, LM609, and anti-avB5, P1F6) and five reference peptides have been evaluated for IC50 determination. Briefly, the method involves immobilizing previously isolated receptors in 96 well plates and incubating overnight. The receptors were isolated from normal, fresh, non-infectious (HIV, hepatitis B and C, syphilis, and HTLV free) human placenta. The tissue was lysed and tissue debris removed via centrifugation. The lysate was filtered. The receptors were isolated by affinity chromatography using the immobilized avb3 antibody. The plates are then washed 3×with wash buffer. Blocking buffer is added and plates incubated for 120 minutes at room temperature. During this time compounds to be tested and [I-125] vitronectin are premixed in a reservoir plate. Blocking buffer is removed and compound mixture pipetted. Competition is carried out for 60 minutes at room temperature. Unbound material is then removed and wells are separated and counted via gamma scintillation.

Oncomouse® Imaging

The study involves the use of the c-Neu Oncomouse® and FVB mice simultaneously as controls. The mice are anesthetized with sodium pentobarbital and injected with approximately 0.5 mCi of radiopharmaceutical. Prior to injection, the tumor locations on each Oncomouse® are recorded and tumor size measured using calipers. The animals are positioned on the camera head so as to image the anterior or posterior of the animals. 5 Minute dynamic images are acquired serially over 2 hours using a 256×256 matrix and a zoom of 2×. Upon completion of the study, the images are evaluated by circumscribing the tumor as the target region of interest (ROI) and a background site in the neck area below the carotid salivary glands.

This model can also be used to assess the effectiveness of the radiopharmaceuticals of the present invention comprised of a beta, alpha or Auger electron emitting isotope. The radiopharmaceuticals are administered in appropriate amounts and the uptake in the tumors can be quantified either non-invasively by imaging for those isotopes with a coincident imageable gamma emission, or by excision of the tumors and counting the amount of radioactivity present by standard techniques. The therapeutic effect of the radiopharmaceuticals can be assessed by monitoring the rate of growth of the tumors in control mice versus those in the mice administered the radiopharmaceuticals of the present invention.

This model can also be used to assess the compounds of the present invention comprised of paramagnetic metals as MRI contrast agents. After administration of the appropriate amount of the paramagnetic compounds, the whole animal can be placed in a commercially available magnetic resonance imager to image the tumors. The effectiveness of the contrast agents can be readily seen by comparison to the images obtain from animals that are not administered a contrast agent.

This model can also be used to assess the compounds of the present invention comprised of heavy atoms as X-ray contrast agents. After administration of the appropriate amount of the X-ray absorbing compounds, the whole animal can be placed in a commercially available X-ray imager to image the tumors. The effectiveness of the contrast agents can be readily seen by comparison to the images obtain from animals that are not administered a contrast agent.

This model can also be used to assess the compounds of the present invention comprised of an echogenic gas containing surfactant microsphere as ultrasound contrast agents. After administration of the appropriate amount of the echogenic compounds, the tumors in the animal can be imaging using an ultrasound probe held proximate to the tumors. The effectiveness of the contrast agents can be readily seen by comparison to the images obtain from animals that are not administered a contrast agent.

Rabbit Matrigel Model

This model was adapted from a matrigel model intended for the study of angiogenesis in mice. Matrigel (Becton & Dickinson, USA) is a basement membrane rich in laminin, collagen IV, entactin, HSPG and other growth factors. When combined with growth factors such as bFGF [500 ng/ml] or VEGF [2 μg/ml] and injected subcutaneously into the mid-abdominal region of the mice, it solidifies into a gel and stimulates angiogenesis at the site of injection within 4-8 days. In the rabbit model, New Zealand White rabbits (2.5-3.0 kg) are injected with 2.0 ml of matrigel, plus 1 μg bFGF and 4 μg VEGF. The radiopharmaceutical is then injected 7 days later and the images obtained.

This model can also be used to assess the effectiveness of the radiopharmaceuticals of the present invention comprised of a beta, alpha or Auger electron emitting isotope. The radiopharmaceuticals are administered in appropriate amounts and the uptake at the angiogenic sites can be quantified either non-invasively by imaging for those isotopes with a coincident imageable gamma emission, or by excision of the angiogenic sites and counting the amount of radioactivity present by standard techniques. The therapeutic effect of the radiopharmaceuticals can be assessed by monitoring the rate of growth of the angiogenic sites in control rabbits versus those in the rabbits administered the radiopharmaceuticals of the present invention.

This model can also be used to assess the compounds of the present invention comprised of paramagnetic metals as MRI contrast agents. After administration of the appropriate amount of the paramagnetic compounds, the whole animal can be placed in a commercially available magnetic resonance imager to image the angiogenic sites. The effectiveness of the contrast agents can be readily seen by comparison to the images obtain from animals that are not administered a contrast agent.

This model can also be used to assess the compounds of the present invention comprised of heavy atoms as X-ray contrast agents. After administration of the appropriate amount of the X-ray absorbing compounds, the whole animal can be placed in a commercially available X-ray imager to image the angiogenic sites. The effectiveness of the contrast agents can be readily seen by comparison to the images obtain from animals that are not administered a contrast agent.

This model can also be used to assess the compounds of the present invention comprised of an echogenic gas containing surfactant microsphere as ultrasound contrast agents. After administration of the appropriate amount of the echogenic compounds, the angiogenic sites in the animal can be imaging using an ultrasound probe held proximate to the tumors. The effectiveness of the contrast agents can be readily seen by comparison to the images obtain from animals that are not administered a contrast agent.

Canine Spontaneous Tumor Model

Adult dogs with spontaneous mammary tumors were sedated with xylazine (20 mg/kg)/atropine (1 ml/kg). Upon sedation the animals were intubated using ketamine (5 mg/kg)/diazepam (0.25 mg/kg) for full anethesia. Chemical restraint was continued with ketamine (3 mg/kg)/xylazine (6 mg/kg) titrating as necessary. If required the animals were ventilated with room air via an endotrachael tube (12 strokes/min, 25 ml/kg) during the study. Peripheral veins were catheterized using 20G I.V. catheters, one to serve as an infusion port for compound while the other for exfusion of blood samples. Heart rate and EKG were monitored using a cardiotachometer (Biotech, Grass Quincy, Mass.) triggered from a lead II electrocardiogram generated by limb leads. Blood samples are generally taken at ˜10 minutes (control), end of infusion, (1 minute), 15 min, 30 min, 60 min, 90 min, and 120 min for whole blood cell number and counting. Radiopharmaceutical dose was 300 μCi/kg administered as an i.v. bolus with saline flush. Parameters were monitored continuously on a polygraph recorder (Model 7E Grass) at a paper speed of 10 mm/min or 10 mm/sec.

Imaging of the laterals were for 2 hours with a 256×256 matrix, no zoom, 5 minute dynamic images. A known source is placed in the image field (20-90 μCi) to evaluate region of interest (ROI) uptake. Images were also acquired 24 hours post injection to determine retention of the compound in the tumor. The uptake is determined by taking the fraction of the total counts in an inscribed area for ROI/source and multiplying the known μCi. The result is μCi for the ROI.

This model can also be used to assess the effectiveness of the radiopharmaceuticals of the present invention comprised of a beta, alpha or Auger electron emitting isotope. The radiopharmaceuticals are administered in appropriate amounts and the uptake in the tumors can be quantified either non-invasively by imaging for those isotopes with a coincident imageable gamma emission, or by excision of the tumors and counting the amount of radioactivity present by standard techniques. The therapeutic effect of the radiopharmaceuticals can be assessed by monitoring the size of the tumors over time.

This model can also be used to assess the compounds of the present invention comprised of paramagnetic metals as MRI contrast agents. After administration of the appropriate amount of the paramagnetic compounds, the whole animal can be placed in a commercially available magnetic resonance imager to image the tumors. The effectiveness of the contrast agents can be readily seen by comparison to the images obtain from animals that are not administered a contrast agent.

This model can also be used to assess the compounds of the present invention comprised of heavy atoms as X-ray contrast agents. After administration of the appropriate amount of the X-ray absorbing compounds, the whole animal can be placed in a commercially available X-ray imager to image the tumors. The effectiveness of the contrast agents can be readily seen by comparison to the images obtain from animals that are not administered a contrast agent.

This model can also be used to assess the compounds of the present invention comprised of an echogenic gas containing surfactant microsphere as ultrasound contrast agents. After administration of the appropriate amount of the echogenic compounds, the tumors in the animal can be imaging using an ultrasound probe held proximate to the tumors. The effectiveness of the contrast agents can be readily seen by comparison to the images obtain from animals that are not administered a contrast agent.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

What is claimed is:
 1. A compound of formula: (Q)_(d)—L_(n)—C_(h) or (Q)_(d)—L_(n)d—(C_(h))_(d), wherein: Q is a compound of Formula Ia:

 or pharmaceutically acceptable salt forms thereof, wherein: X^(1d), X^(2d), X^(3d), and X^(4d) are independently selected from nitrogen or carbon provided that at least two of X^(1d), X^(2d), X^(3d) and X^(4d) are carbon; R^(1d) is selected from:

A^(d) and B^(d) are independently —CH₂—, —O—, —N(R^(2d))—, or —C(═O)—; A^(1d) and B^(1d) are independently —CH₂— or —N(R^(3d))—; D^(d) nis —N(R^(2d))—, —O—, —S—, —C(═O)— or —SO₂—; E^(d—F) ^(d) is —C(R^(4d))═C(R^(5d))—, —N═C(R^(4d))—, —C(R^(4d))═N—, or —C(R^(4d))₂C(R^(5d))₂—; J^(d), K^(d), L^(d) and M^(d) are independently selected from —C(R^(4d))—, —C(R^(5d))— or —N—, provided that at least one of J^(d), K^(d), L^(d) and M^(d) is not —N—; R^(2d) is selected from: H, C₁-C₆ alkyl, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl; (C₁-C₆ alkyl)aminocarbonyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, heteroaryl(C₁-C₆ alkyl)carbonyl, heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl—, arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl, aryloxycarbonyl, or aryl(C₁-C₆ alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro; R^(3d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₁-C₆ alkyl)-; R^(4d) and R^(5d) are independently selected from: H, C₁-C₄ alkoxy, NR^(2d)R^(3d), halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl, or alternatively, when substituents on adjacent atoms, R^(4d) and R^(5d) can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃, or NO₂; U^(d) is selected from: —(CH₂)_(n) ^(d)—, —(CH₂)_(n) ^(d)(CR^(7d)═CR^(8d))(CH₂)_(m) ^(d)—, —(CH₂)_(n) ^(d)(C═C)(CH₂)_(m) ^(d)—, —(CH₂)_(t) ^(d)Q(CH₂)_(m) ^(d)—, —(CH₂)_(n) ^(d)O(CH₂)_(m) ^(d)—, —(CH₂)_(n) ^(d)N(R^(6d))(CH₂)_(m) ^(d)— —(CH₂)_(n) ^(d)C(═O)(CH₂)_(m) ^(d)—, —(CH₂)_(n) ^(d)(C═O)N(R^(6d))(CH₂)_(m) ^(d)— —(CH₂)_(n) ^(d)N(R^(6d))(C═O)(CH₂)_(m) ^(d)—, or —(CH₂)_(n) ^(d)S(O)_(p) ^(d)(CH₂)_(m) ^(d)—; wherein one or more of the methylene groups in U^(d) is optionally substituted with R^(7d); Q^(d) is selected from 1,2-cycloalkylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 2,4-pyridinylene, or 3,4-pyridazinylene; R^(6d) is selected from: H, C₁-C₄ alkyl, or benzyl; R^(7d) and R^(8d) are independently selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₀-C₆ alkyl)-; R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), N(R^(6d))₂, halogen, NO₂, CN, CF₃, CO₂R^(17d), C(═O)R^(17d), CONR^(17d)R^(20d), —SO₂R^(17d), —SO₂NR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₆ alkenyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₇ cycloalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₄-C₁₁ cycloalkylalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), aryl substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d), or aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d); R^(11d) is selected from H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)R^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d); W^(d) is selected from: —C(R^(12d))₂)_(q) ^(d)C(═O)N(R^(13d))—, or —C(═O)—N(R^(13d))—(C(R^(12d))₂)_(q) ^(d)—; X^(d) is —C(R^(12d))(R^(14d))—C(R^(12d))(R^(15d))—; or alternatively, W^(d) and X^(d) can be taken together to be

R^(12d) is selected from H, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₄-C₁₀ cycloalkylalkyl, (C₁-C₄ alkyl)carbonyl, aryl, or aryl(C₁-C₆ alkyl)-; R^(13d) is selected from H, C₁-C₆ alkyl, C₃-C₇ cycloalkylmethyl, or aryl(C₁-C₆ alkyl)-; R^(14d) is selected from: H, C₁-C₆ alkylthio(C₁-C₆ alkyl)-, aryl(C₁-C₁₀ alkylthioalkyl)-, aryl(C₁-C₁₀ alkoxyalkyl)-, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₆ hydroxyalkyl, C₂-C₁₀ alkenyl, C₂—C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, heteroaryl(C₁-C₆ alkyl)-, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), or CONR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0-1 R^(16d) or 0-2 R^(11d); R^(15d) is selected from: H, R^(16d), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ alkylaminoalkyl, C₁-C₁₀ dialkylaminoalkyl, (C₁-C₁₀ alkyl)carbonyl, aryl(C₀-C₆ alkyl)carbonyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl ,C₃—C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, heteroaryl(C₁-C₆ alkyl)-, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), CONR^(17d)R^(20d), SO₂R^(17d), or SO₂NR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0-2 R^(11d); Y^(d) is selected from: —COR^(19d), —SO₃H, —PO₃H, tetrazolyl, —CONHNHSO₂CF₃, —CONHSO₂R^(17d), —CONHSO₂NHR^(17d), —NHCOCF₃, —NHCONHSO₂R^(17d), —NHSO₂R^(17d), —OPO₃H₂, —OSO₃H, —PO₃H₂, —SO₃H, —SO₂NHCOR^(17d), —SO₂NHCO₂R^(17d),

R^(16d) is selected from: —N(R^(20d))—C(═O)—O—R^(17d), —N(R^(20d))—C(═O)—R^(17d), —N(R^(20d))—C(═O)—NH—R^(17d), —N(R^(20d))SO₂—R^(17d), or —N(R^(20d))SO₂—NR^(20d)R^(17d); R^(17d) is selected from: C₁-C₁₀ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁ cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)aryl optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to L_(n), biaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), heteroaryl optionally substituted with a bond to L_(n), aryl optionally substituted with a bond to L_(n), or a bond to L_(n), wherein said aryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, heteroaryl, halo, cyano, amino, CF₃, and NO₂; R^(18d) is selected from: H, —C(═O)—O—R^(17d), —C(═O)—R^(17d), —C(═O)—NH—R^(17d), —SO₂—R^(17d), or —SO₂—NR^(20d)R^(17d); R^(19d) is selected from: hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy, aryloxy, aryl(C₁-C₆ alkoxy), C₃-C₁₀ alkylcarbonyloxyalkyloxy, C₃-C₁₀ alkoxycarbonyloxyalkyloxy, C₂-C₁₀ alkoxycarbonylalkyloxy, C₅-C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonylalkyloxy, C₇-C₁₁ aryloxycarbonylalkyloxy, C₈-C₁₂ aryloxycarbonyloxyalkyloxy, C₈-C₁₂ arylcarbonyloxyalkyloxy, C₅-C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅-C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀—C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R^(11d))(R^(12d))N—(C₁-C₁₀ alkoxy); R^(20d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₁-C₆ alkyl)-; R^(21d) is selected from: COOH or N(R^(6d))₂; m^(d) is 0-4; n^(d) is 0-4; t^(d) is 0-4; p^(d) is 0-2; q^(d) is 0-2; and r^(d) is 0-2; with the following provisos: (1)_(t) ^(d), n^(d), m^(d) and q^(d) are chosen such that the number of atoms connecting R^(1d) and y^(d) is in the range of 10-14; and (2)_(n) ^(d) and m^(d) are chosen such that the value of n_(d) plus m^(d) is greater than one unless U^(d) is —(CH₂)_(t) ^(d)Q^(d)(CH₂)_(m) ^(d)—; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; L_(n) is a linking group having the formula: (CR⁶R⁷)_(g)—(W)_(h)—(CR^(6a)R^(7a))_(g′)—(Z)_(k)—(W)_(h′)—(CR⁸R⁹)_(g″)—(W)_(h″)—(CR^(8a)R^(9a))_(g″′—(W)) _(h″′)—(CR^(8b)R^(9b))_(g″″—;) W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, SO₂NH, (OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), (CH₂CH₂CH₂O)_(t), and (aa)_(t′); aa is independently at each occurrence an amino acid; Z is selected from the group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R^(8b), R⁹, R^(9a) and R^(9b) are independently selected at each occurrence from the group: H, ═O, COOH, SO₃H, PO₃H, C₁-C₅ alkyl substituted with 0-3 R¹⁰, aryl substituted with 0-3 R¹⁰, benzyl substituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹ and a bond to C_(h); R¹⁰ is independently selected at each occurrence from the group: a bond to C_(h), COOR¹¹, C(═O)NHR¹¹, NHC(═O)R¹¹, OH, NHR¹¹, SO₃H, PO₃H, —OPO₃H₂, —OSO₃H, aryl substituted with 0-3 R¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1 R¹², and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹¹; R¹¹ is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R¹², aryl substituted with 0-1 R¹², a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycol substituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹², cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1 R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substituted with 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C_(h); R¹² is a bond to C_(h); k is selected from 0, 1, and 2; h is selected from 0, 1, and 2; h′ is selected from 0, 1, 2, 3, 4, and 5; h″ is selected from 0, 1, 2, 3, 4, and 5; h″′ is selected from 0, 1, 2, 3, 4, and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; C_(h) is a metal bonding unit having a formula selected from the group:

A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at each occurrence from the group: NR¹³, NR¹³R¹⁴, S, SH, S(Pg), O, OH, PR¹³, PR¹³R¹⁴, P(O)R¹⁵R¹⁶, and a bond to L_(n); E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀ aryl—C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷; R¹³ and R¹⁴ are each independently selected from the group: a bond to L_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₁₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³ or R¹⁴ is an electron, then the other is also an electron; alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹); R¹⁵ and R¹⁶ are each independently selected from the group: a bond to L_(n), —OH, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷; R¹⁷ is independently selected at each occurrence from the group: a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸, —C(═O)R¹⁸, —C(═O)N(R¹⁸)₂, —CHO, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)OR^(18a), —OR¹⁸, —OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂, —NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —SR¹⁸, —S(═O)R^(18a), —SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, NO₂, —C(═O)NHOR¹⁸, —C(═O)NHNR¹⁸R^(18a), —OCH₂CO₂H, 2-(1-morpholino)ethoxy, C₁-C₅ alkyl, C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylmethyl, C₂-C₆ alkoxyalkyl, aryl substituted with 0-2 R¹⁸, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O; R¹⁸, R^(18a), and R¹⁹ are independently selected at each occurrence from the group: a bond to L_(n), H, C₁-C₆ alkyl, phenyl, benzyl, C₁-C₆ alkoxy, halide, nitro, cyano, and trifluoromethyl; Pg is a thiol protecting group; R²⁰ and R²¹ are independently selected from the group: H, C₁-C₁₀ alkyl, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, C₂-C₁₀ 1-alkene substituted with 0-3 R²³, C₂-C₁₀ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3 R²³, unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R²³, and unsaturated C₃₋₁₀ carbocycle substituted with 0-3 R²³; alternatively, R²⁰ and R²¹, taken together with the divalent carbon radical to which they are attached form:

R²² and R²³ are independently selected from the group: H, R²⁴, C₁-C₁₀ alkyl substituted with 0-3 R²⁴, C₂-C₁₀ alkenyl substituted with 0-3 R²⁴, C₂-C₁₀ alkynyl substituted with 0-3 R²⁴, aryl substituted with 0-3 R²⁴, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R²⁴, and C₃₋₁₀ carbocycle substituted with 0-3 R²⁴; alternatively, R²², R²³ taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O; a and b indicate the positions of optional double bonds and n is 0 or 1; R²⁴ is independently selected at each occurrence from the group: ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, —N(R²⁵)3+, —CH₂OR²⁵, —OC(═O)R²⁵, —OC(═O)OR^(25a), —OR²⁵, —OC(═O)N(R²⁵)₂, —NR²⁶C(═O)R²⁵, NR²⁶C(═O)OR^(25a), —NR²⁶C(═O)N(R²⁵)₂, —NR²⁶SO₂N(R²⁵)₂, —NR²⁶SO₂R^(25a), —SO₃H, —SO₂R^(25a), —SR²⁵, S(═O)R^(25a), —SO₂N(R²⁵)₂, —N(R²⁵)₂, ═NOR²⁵, —C(═O)NHOR²⁵, —OCH₂CO₂H, and 2-(1-morpholino)ethoxy; and, R²⁵, R^(25a), and R²⁶ are each independently selected at each occurrence from the group: hydrogen and C₁-C₆.
 2. A compound according to claim 1, wherein: Q is a compound of Formula Ia:

 or pharmaceutically acceptable salt forms thereof, wherein: X^(1d), X^(2d), X^(3d), and X^(4d) are independently selected from nitrogen or carbon provided that at least two of X^(1d), X^(2d), X^(3d) and X^(4d) are carbon; R^(1d) is selected from:

 alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro; R^(3d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₁-C₆ alkyl)-; R^(4d) and R^(5d) are independently selected from: H, C₁-C₄ alkoxy, NR^(2d)R^(3d), halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, C₂-C₇ alkylcarbonyl, arylcarbonyl or alternatively, when substituents on adjacent atoms, R^(4d) and R^(5d) can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃, or NO₂;U^(d) is selected from: —(CH₂)_(n) ^(d)—, —(CH₂)_(n) ^(d)(CR^(7d)═CR^(8d))(CH₂)_(m) ^(d)—, —(CH₂)_(t) ^(d)Q^(d)(CH₂)_(m) ^(d), —(CH₂)_(n) ^(d)O(CH₂)_(m) ^(d), —(CH₂)_(n) ^(d)N(R^(6d))(CH₂)_(m) ^(d)—, —(CH₂)_(n) ^(d)C(═O)(CH₂)_(m) ^(d)—, or —(CH₂)_(n) ^(d)S(O)_(p) ^(d)(CH₂)_(m) ^(d); wherein one or more of the methylene groups in U^(d) is optionally substituted with R^(7d); Q^(d) is selected from 1,2-phenylene, 1,3-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, or 2,4-pyridinylene; R^(6d) is selected from: H, C₁-C₄ alkyl, or benzyl; A^(d) and B^(d) are independently —CH₂—, —O—, —N(R^(2d))—, or —C(═O)—; A^(1d) and B^(1d) are independently —CH₂— or —N(R^(3d))—; D^(d) is —N(R^(2d))—, —O—, —S—, —C(═O)— or —SO₂—; E^(d)-F^(d) is —C(R^(4d))═C(R^(5d)), —N═C(R^(4d))—, —C(R^(4d))═N—, or —C(R^(4d))₂C(R^(5d))₂—; J^(d), K^(d), L^(d) and M^(d) are independently selected from —C(R^(4d))—, —C(R^(5d))— or —N—, provided that at least one of J^(d), K^(d), L^(d) and M^(d) is not —N—; R^(2d) is selected from: H, C₁-C₆ alkyl, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, C₁-C₆ alkylaminocarbonyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, heteroaryl(C₁-C₆ alkyl)carbonyl, heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl, aryloxycarbonyl, or aryl(C₁-C₆ alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C₁-C₄ R^(7d) and R^(8d) are independently selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₀-C₆ alkyl)-; R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), N(R^(6d))₂, halogen, NO₂, CN, CF₃, CO₂R^(17d)C(═O)R^(17d), CONR^(17d)R^(20d), —SO₂R^(17d), —SO₂NR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₆ alkenyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₇ cycloalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₄-C₁₁ cycloalkylalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), aryl substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d), or aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d); R^(11d) is selected from: H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)Rd^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d); W^(d) is —C(═O)—N(R^(13d))—(C(R^(12d))₂)_(q) ^(d)—; X^(d) is —C(R^(12d))(R^(14d))—C(R^(12d))(R^(15d))—; alternatively, W^(d) and X^(d) can be taken together to be

R^(12d) is H or C₁-C₆ alkyl; R^(13d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkylmethyl, or aryl(C₁-C₆ alkyl)-; R^(14d) is selected from: H, C₁-C₆ alkylthioalkyl, aryl(C₁-C₁₀ alkylthioalkyl)-, aryl(C₁-C₁₀ alkoxyalkyl)-, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₆ hydroxyalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, heteroaryl(C₁-C₆ alkyl)-, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), or CONR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be substituted independently with 0-1 R^(16d) or 0-2 R^(11d); R^(15d) is selected from: H, R^(16d), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ alkylaminoalkyl, C₁-C₁₀ dialkylaminoalkyl, C₁-C₁₀ alkylcarbonyl, aryl(C₀-C₆ alkyl)carbonyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, heteroaryl(C₁-C₆ alkyl)-, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), CONR^(17d)R^(20d), SO₂R^(17d), or SO₂NR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be substituted independently with 0-2 R^(11d); Y^(d) is selected from: —COR^(19d), —SO₃H,

R^(16d) is selected from: —N(R^(20d))—C(═O)—O—R^(17d), —N(R^(20d))—C(═O)—R^(17d), —N(R^(20d))—C(═O)—NH—R^(17d), —N(R^(20d))SO₂—R^(17d), or —N(R^(20d))SO₂—NR^(20d)R^(17d); R^(17d) is selected from: C₁-C₁₀ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁ cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)aryl optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to L_(n), biaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), heteroaryl optionally substituted with a bond to L_(n), aryl optionally substituted with a bond to L_(n), or a bond to L_(n), wherein said aryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, heteroaryl, halo, cyano, amino, CF₃, and NO₂; R^(18d) is selected from: H, —C(═O)—O—R^(17d), —C(═O)—R^(17d), —C(═O)—NH—R¹⁷, —SO₂—R^(17d), or —SO₂—NR^(20d)R^(17d); R^(19d) is selected from: hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy, C₆-C₁₀ aryloxy, C₇-C₁₁ aralkyloxy, C₃-C₁₀ alkylcarbonyloxyalkyloxy, C₃-C₁₀ alkoxycarbonyloxyalkyloxy, C₂-C₁₀ alkoxycarbonylalkyloxy, C₅-C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonylalkyloxy, C₇-C₁₁ aryloxycarbonylalkyloxy, C₈-C₁₂ aryloxycarbonyloxyalkyloxy, C₈-C₁₂ arylcarbonyloxyalkyloxy, C₅-C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅-C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀-C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R^(11d))(R^(12d))N—(C₁-C₁₀ alkoxy)-; R^(20d) selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₁-C₆ alkyl)-; R^(21d) is selected from COOH or N(R^(6d))₂; m^(d) is 0-4; n^(d) is 0-4; p^(d) is 0-2; q^(d) is 0-2; t^(d) is 0-4; r^(d) is 0-2; d is selected from 1, 2, 3, 4, and 5; W is independently selected at each occurrence from the group: O, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, (OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), and (CH₂CH₂CH₂O)_(t); Z is selected from the group: aryl substituted with 0-1 R¹⁰, C₃₋₁₀ cycloalkyl substituted with 0-1 R¹⁰, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R^(8b), R⁹, R^(9a) and R^(9b) are independently selected at each occurrence from the group: H, ═O, COOH, SO₃H, C₁-C₅ alkyl substituted with 0-1 R¹⁰, aryl substituted with 0-1 R¹⁰, benzyl substituted with 0-1 R¹⁰, and C₁-C₅ alkoxy substituted with 0-1 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to C_(h); R¹⁰ is independently selected at each occurrence from the group: a bond to C_(h), COOR¹¹, C(═O)NHR¹¹, NHC(═O)R¹¹, OH, NHR¹¹, SO₃H, PO₃H, —OPO₃H₂, —OSO₃H, aryl substituted with 0-3 R¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1 R¹², and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹¹; R¹¹ is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R¹², aryl substituted with 0-1 R¹², a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycol substituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹², cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1 R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substituted with 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C_(h); k is 0 or 1; s is selected from 0, 1, 2, 3, 4, and 5; s′ is selected from 0, 1, 2, 3, 4, and 5; s″ is selected from 0, 1, 2, 3, 4, and 5; t is selected from 0, 1, 2, 3, 4, and 5; A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at each occurrence from the group: NR¹³, NR¹³R¹⁴, S, SH, S(Pg), OH, and a bond to L_(n); E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷; R¹³ and R¹⁴ are each independently selected from the group: a bond to L_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³ or R¹⁴ is an electron, then the other is also an electron; alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹); R¹⁷ is independently selected at each occurrence from the group: a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸, —C(═O)R¹⁸, —C(═O)N(R¹⁸)₂, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)OR^(18a), —OR¹⁸, —OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂, —NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —S(═O)R^(18a), —SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, —C(═O)NHNR¹⁸R^(18a), —OCH₂CO₂H, and 2-(1-morpholino)ethoxy; R¹⁸, R^(18a), and R¹⁹ are independently selected at each occurrence from the group: a bond to L_(n), H, and C₁-C₆ alkyl; R²⁰ and R²¹ are independently selected from the group: H, C₁-C₅ alkyl, —CO₂R²⁵, C₂-C₅ 1-alkene substituted with 0-3 R²³, C₂-C₅ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3 R²³, and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R²³; alternatively, R²⁰ and R²¹, taken together with the divalent carbon radical to which they are attached form:

R²² and R²³ are independently selected from the group: H, and R²⁴; alternatively, R²², R²³ taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O; R²⁴ is independently selected at each occurrence from the group: —CO₂R²⁵, —C(═O)N(R²⁵)₂, —CH₂OR²⁵, —OC(═O)R²⁵, —OR²⁵, —SO₃H, —N(R²⁵)₂, and —OCH₂CO₂H; and, R²⁵ is independently selected at each occurrence from the group: H and C₁-C₃ alkyl.
 3. A compound according to claim 2, wherein: Q is a compound of Formula IIa or IIb:

 or pharmaceutically acceptable salt forms thereof wherein: X^(1d) and X^(3d) are independently selected from nitrogen or carbon; R^(1d) is selected from:

 wherein the above heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH₂, halogen, NO₂, CN, CF₃, C₁-C₄ alkoxy, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; U^(d) is —(CH₂)_(n)—, —(CH₂)_(t) ^(d)Q^(d) (CH₂)_(m) ^(d)— or —C(═O)(CH₂)_(n) ^(d)—1⁻, wherein one of the methylene groups is optionally substituted with R^(7d); Q^(d) is selected from 1,2-phenylene, 1,3-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, or 2,4-pyridinylene; R^(6d) is selected from: H, C₁-C₄ alkyl, or benzyl; R^(7d) is selected from: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl), heteroaryl, or heteroaryl(C₁-C₆ alkyl); R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), halogen, CO₂R^(17d), CONR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₇ cycloalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₄-C₁₁ cycloalkylalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), or aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d); R^(11d) is selected from: H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)R^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d); W^(d) is —C(═O)—N(R^(13d))—; X^(d) is —CH(R^(14d))—CH(R^(15d))—; R^(13d) is H or CH₃; R^(14d) is selected from: H, C₁-C₁₀ alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, halo, cyano, amino, CF₃, and NO₂; R^(15d) is H or R^(16d); Y_(d) is —COR^(19d); R^(16d) is selected from: —NH(R^(20d))—C(═O)—O—R^(17d), —N(R^(20d))—C(═O)—R^(17d), —N(R^(20d))—C(═O)—NH—R^(17d), —N(R^(20d))SO₂—R^(17d), or —N(R^(20d))SO₂—N(R^(20d))R^(17d); R^(17d) is selected from: C₁-C₁₀ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁ cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)aryl optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to L_(n), biaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), heteroaryl optionally substituted with a bond to L_(n), aryl optionally substituted with a bond to L_(n), or a bond to L_(n), wherein said aryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, heteroaryl, halo,cyano, amino, CF₃, and NO₂; R^(19d) is selected from: hydroxy, C₁-C₁₀ alkoxy, methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy-, t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy-, 1-(methylcarbonyloxy)ethoxy-, 1-(ethylcarbonyloxy)ethoxy-, 1-(t-butylcarbonyloxy)ethoxy-, 1-(cyclohexylcarbonyloxy)ethoxy-, i-propyloxycarbonyloxymethoxy-, t-butyloxycarbonyloxymethoxy-, 1-(i-propyloxycarbonyloxy)ethoxy-, 1-(cyclohexyloxycarbonyloxy)ethoxy-, 1-(t-butyloxycarbonyloxy)ethoxy-, dimethylaminoethoxy-, diethylaminoethoxy-, (5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-, (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-, (1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-, or 1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-; R^(20d) is H or CH₃; R^(21d) is selected from COOH or N(R^(6d))₂; m^(d) is 0 or 1; n^(d) is 1-4; t^(d) is 0 or 1; or Q is a peptide selected from the group:

R¹ is L-valine, D-valine or L-lysine optionally substituted on the α amino group with a bond to L_(n); R² is L-phenylalanine, D-phenylalanine, D-1-naphthylalanine, 2-aminothiazole-4-acetic acid or tyrosine, the tyrosine optionally substituted on the hydroxy group with a bond to L_(n); R³ is D-valine; R⁴ is D-tyrosine substituted on the hydroxy group with a bond to L_(n); provided that one of R¹ and R² in each Q is substituted with a bond to L_(n), and further provided that when R² is 2-aminothiazole-4-acetic acid, K is N-methylarginine; d is 1, 2, 3, 4, or 5; provided that at least one Q is a compound of Formula IIa or IIb; C_(h) is

A¹ is selected from the group: OH, and a bond to L_(n); A², A⁴, and A⁶ are each N; A³, A⁵, and A⁸ are each OH; A⁷ is a bond to L_(n) or NH-bond to L_(n); E is a C₂ alkyl substituted with 0-1 R¹⁷; R¹⁷ is ═O; alternatively, C_(h) is

A¹ is selected from the group: OH, and a bond to L_(n); A², A³ and A⁴ are each N; A⁵, A⁶ and A⁸ are each OH; A⁷ is a bond to L_(n); E is a C₂ alkyl substituted with 0-1 R¹⁷; R¹⁷ is ═O; alternatively, C_(h) is

A¹ is NH₂ or N═C(R²⁰)(R²¹); E is a bond; A² is NHR¹³; R¹³ is a heterocycle substituted with R¹⁷, the heterocycle being selected from pyridine and pyrimidine; R¹⁷ is selected from a bond to L_(n), C(═O)NHR¹⁸ and C(═O)R¹⁸; R¹⁸ is a bond to L_(n); R²⁴ is selected from the group: —CO₂R²⁵, —OR²⁵, —SO₃H, and —N(R²⁵)₂; and, R²⁵ is independently selected at each occurrence from the group: hydrogen and methyl.
 4. A compound according to claim 3, Q is a compound of Formula IIa or IIb:

or pharmaceutically acceptable salt forms thereof wherein: X^(1d) and X^(3d) are independently selected from nitrogen or carbon, provided that at least one of X^(1d) and X^(3d) is carbon; R^(1d) is selected from:

 wherein the above heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH₂, halogen, NO₂, CN, CF₃, C₁-C₄ alkoxy, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; U^(d) is —(CH₂)_(n)—, —(CH₂)_(t) ^(d)Q^(d)(CH₂)_(m) ^(d)— or —C(═O)(CH₂)_(n) ^(d)1⁻, wherein one of the methylene groups is optionally substituted with R^(7d); Q^(d) is selected from 1,2-phenylene, 1,3-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, or 2,4-pyridinylene; R^(6d) is selected from: H, C₁-C₄ alkyl, or benzyl; R^(7d) is selected from: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl), heteroaryl, or heteroaryl(C₁-C₆ alkyl); R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), halogen, CO₂R^(17d), CONR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₇ cycloalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₄-C₁₁ cycloalkylalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), or aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d); R^(11d) is selected from: H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)R^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d);W is —C(═O)—N(R^(13d))—; W^(d) is —C(═O)—N(R^(13d)); X^(d) is —CH(R^(14d))—CH(R^(15d))—; R^(13d) is H or CH₃; R^(14d) is selected from: H, C₁-C₁₀ alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, halo, cyano, amino, CF₃, and NO₂; R^(15d) is H or R^(16d); Y^(d) is —COR^(19d); R^(16d) is selected from: —N(R^(20d))—C(═O)—O—R^(17d), —N(R^(20d))—C(═O)—R^(17d), —N(R^(20d))—C(═O)—NH—R^(17d), —N(R^(20d))SO₂—R^(17d), or —N(R^(20d))SO₂—NR^(20d)R^(17d); R^(17d) is selected from: C₁-C₁₀ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁ cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)aryl optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to L_(n), biaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), heteroaryl optionally substituted with a bond to L_(n), aryl optionally substituted with a bond to L_(n), or a bond to L_(n), wherein said aryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, heteroaryl, halo,cyano, amino, CF₃, and NO₂; R^(19d) is selected from: hydroxy, C₁-C₁₀ alkoxy, methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy-, t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy-, 1-(methylcarbonyloxy)ethoxy-, 1-(ethylcarbonyloxy)ethoxy-, 1-(t-butylcarbonyloxy)ethoxy-, 1-(cyclohexylcarbonyloxy)ethoxy-, i-propyloxycarbonyloxymethoxy-, t-butyloxycarbonyloxymethoxy-, 1-(i-propyloxycarbonyloxy)ethoxy-, 1-(cyclohexyloxycarbonyloxy)ethoxy-, 1-(t-butyloxycarbonyloxy)ethoxy-, dimethylaminoethoxy-, diethylaminoethoxy-, (5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-, (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-, (1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-, or 1-(2-(2-methoxypropyl)carbonyloxy)ethoxy; R^(20d) is H or CH₃; R^(21d) is selected from COOH or N(R^(6d))₂; m^(d) is 0 or 1; n^(d) is 1-4; and t^(d) is 0 or
 1. 5. A compound according to claim 1, wherein the compound is selected from the group: 2-(((4-(4-(((3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid; 2-(2-aza-2-((5-(N-(1,3-bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propyl)carbamoyl)(2-pyridyl))amino)vinyl)benzenesulfonic acid; 2-((6-((1-aza-2-(sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)-4-(N-(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)butanoic acid; 3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl1)phenyl)phenyl)sulfonyl)amino)propanoic acid; 2-(6-((6-((1-aza-2-(2-sulfophenyl)vinyl)-amino)(3-pyridyl))carbonylamino)hexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-propanoic acid; 2-((6-((1-aza-2-(2-sulfophenyl)vinyl)-amino)(3-pyridyl))carbonylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid; [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]benzenesulfonic acid]-Glu(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl -amino)propanoic acid); [2-[[[5-[carbonyl]-2-pyridinyl]hydrazono]methyl]benzenesulfonic acid]-Glu-bis-[Glu(2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid)(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)]; 2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-{2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid); 2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-Glu{2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)}{2-(6-Aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid}; DOTA/N,N′-Bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)-2-(amino)pentane-1,5-diamide conjugate; DOTA/2-amino-4-(N-(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)butanoic acid Salt; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-3-(4-(phosphonooxy)phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid Conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-3-(4-(sulfooxy)phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl)) carbonylamino)propionic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(ethyl-3,6-O-disulfo-β-D-galactopyranosyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(6-deoxy-β-cyclodextryl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(ω-methoxypolyethylene(5,000)glycoxyethyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate; 2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-aminohexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid salt; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-6-(2-(bis(phosphonomethyl)amino)acetylamino)hexanolylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate; DTPA adduct of 2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid; or a pharmaceutically acceptable salt form thereof.
 6. A kit comprising a compound of claim 1, or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier.
 7. A kit according to claim 6, wherein the kit further comprises one or more ancillary ligands and a reducing agent.
 8. A kit according to claim 7, wherein the ancillary ligands are tricine and TPPTS.
 9. A kit according to claim 8, wherein the reducing agent is tin(II).
 10. A diagnostic or therapeutic metallopharmaceutical composition, comprising: a compound according to claim 1 and a metal selected from the group consisting of ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, ⁶⁸Ga, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹Pm, ⁹⁰Y, ²¹²Bi, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu, Gd(III), Dy(III), Fe(III), Mn(II), Sm, Ho, Lu, Pm, Y, Bi, Gd, La, Au, Yb, Dy and Cu.
 11. A composition according to claim 10, wherein the metallopharmaceutical is a diagnostic radiopharmaceutical; and the metal is a radioisotope selected from the group: ^(99m)Tc, ⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, and ⁶⁸Ga.
 12. A composition according to claim 11, wherein the radioisotope is ^(99m)Tc or ⁹⁵Tc, and further comprising a first ancillary ligand and a second ancillary ligand capable of stabilizing the radiopharmaceutical.
 13. A composition according to claim 12, wherein the radioisotope is ^(99m)Tc.
 14. A composition according to claim 13, wherein the radiopharmaceutical is selected from the group: ^(99m)Tc ((((4-(4-(((3-(2-(2-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid) (tricine)(TPPTS); ^(99m)Tc (2-(2-((5-(N-(1,3-bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propyl)carbamoyl)(2-pyridyl))2-diazenido) (tricine)(TPPTS); ^(99m)Tc (2-((6-(diazenido)(3-pyridyl))carbonylamino)-4-(N-(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)butanoic acid) (tricine)(TPPTS); ^(99m)Tc (2-(6-((6-(diazenido)(3-pyridyl))carbonylamino)hexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-propanoic acid) (tricine)(TPPTS); ^(99m)Tc (2-((6-(diazenido)(3-pyridyl))carbonylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (tricine)(TPPTS); ^(99m)Tc [2-[[[5-[carbonyl]-2-pyridiny]diazenido]-Glu(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid)(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)) (tricine)(TPPTS); ^(99m)Tc ([2-[[[5-[carbonyl]-2-pyridinyl]diazenido]-Glu-bis-[Glu(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid)(2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid)]) (tricine)(TPPTS)).
 15. A composition according to claim 11, wherein the radioisotope is ¹¹¹In.
 16. A composition according to claim 15, wherein, the radiopharmaceutical is an ¹¹¹In complex of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic Acid.
 17. A composition according to claim 10, wherein the metallopharmaceutical is a therapeutic radiopharmaceutical; and the metal is a radioisotope selected from the group: ¹⁸⁶Re, ¹⁸⁸Re, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹pm, ⁹⁰Y, ²¹²Bi, ¹⁰³Pd, ¹⁰⁹Pd, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu, ¹⁰⁵Rh, ¹¹¹Ag, and ¹⁹²Ir.
 18. A composition according to claim 17, wherein the radioisotope is ¹⁵³Sm.
 19. A composition according to claim 17, wherein the radioisotope is ¹⁷⁷Lu.
 20. A composition according to claim 19, wherein the radiopharmaceutical a ¹⁷⁷Lu complex of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic acid.
 21. A composition according to claim 17, wherein the radioisotope is ⁹⁰Y.
 22. A composition according to claim 21, wherein, the radiopharmaceutical is a ⁹⁰Y complex of 3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic acid.
 23. A composition according to claim 10, wherein the metallopharmaceutical is a MRI contrast agent; and the metal is a paramagnetic metal ion selected from the group: Gd(III), Dy(III), Fe(III), and Mn(II).
 24. A composition according to claim 23, wherein the metal ion is Gd(III).
 25. A composition according to claim 24, wherein the contrast agent is a Gd complex of 3-((1-(3-(Imidazole-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic acid.
 26. A composition according to claim 10, wherein the metallopharmaceutical is a X-ray contrast agent, the metal is selected from the group: Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag, and Ir.
 27. A method of treating rheumatoid arthritis in a patient comprising: administering to said patient a therapeutic radiopharmaceutical of claim 17, capable of localizing in new angiogenic vasculature, by injection or infusion.
 28. A method of treating cancer in a patient comprising: administering to a patient in need thereof a therapeutic radiopharmaceutical of claim 17 by injection or infusion.
 29. A method of imaging formation of new blood vessels in a patient comprising: (1) administering a diagnostic radiopharmaceutical of claim 11 to a patient by injection or infusion; and (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.
 30. A method of imaging cancer in a patient comprising: (1) administering a diagnostic radiopharmaceutical of claim 11 to a patient by injection or infusion; and (2) imaging the patient using planar or SPECT gamma scintigraphy, or positron emission tomography.
 31. A method of imaging cancer in a patient comprising: (1) administering a MRI contrast agent of claim 23; and (2) imaging the patient using magnetic resonance imaging.
 32. A method of imaging cancer in a patient comprising: (1) administering a X-ray contrast agent of claim 26 and (2) imaging the patient using X-ray computed tomography.
 33. A therapeutic radiopharmaceutical composition, comprising: (a) a therapeutic radiopharmaceutical of claim 17; and, (b) a parenterally acceptable carrier.
 34. A composition, comprising: (a) a diagnostic or therapeutic metallopharmaceutical of claim 10, and, (b) a parenterally acceptable carrier.
 35. A compound of the formula: (Q)_(d)—L_(n)—C_(h) or (Q)_(d)—L_(n)—(C_(h))_(d′) wherein: Q is a compound of Formula Ia:

 or pharmaceutically acceptable salt forms thereof, wherein: X^(1d), X^(2d), X^(3d), and X^(4d) are carbon atoms; R^(1d) is selected from:

D^(d) is —N(R^(2d)); E^(d)—F^(d) is —C(R^(4d))═C(R^(5d)); R^(3d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and C₄-C₁₁ cycloalkylalkyl; R^(4d) and R^(5d) are independently hydrogen; U^(d) is —(CH₂)_(n) ^(d)—; R^(6d) is hydrogen; R^(10d) is selected from the group consisting of: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), N(R^(6d))₂, halogen, NO₂, CN, CF₃, CO₂ R^(17d), C(═O)R^(17d), CONR^(17d)R^(20d), —SO₂R^(17d), —SO₂NR^(17d)R^(20d), and C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d); R^(11d) is selected from H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)dR^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d); W^(d) is —C(═O)—N(R^(13d))—(C(R^(12d))₂)_(q) ^(d)−; X^(d) is —C(R^(12d))(R^(14d))—C(R^(12d))(R^(15d))—; R^(12d) is hydrogen; R^(13d) is hydrogen; R^(14d) is hydrogen; R^(15d) is R^(16d); Y^(d) is —COR^(19d); R^(16d) is —N(R^(20d))SO₂—R^(17d); R^(17d) is a bond to L_(n); R^(19d) is hydroxy; R^(20d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl; R^(21d) is selected from: COOH or (NR^(6d))₂; n^(d) is 3; q^(d) is 0; with the following proviso: (1)_(t) ^(d), n^(d), and q^(d) are chosen such that the number of atoms connecting R^(1d) and Y^(d) is in the range of 10-14; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; d′ is 1-100; L_(n) is a linking group having the formula: (CR⁶R⁷)_(g)—(W)_(h)—(CR^(6a)R^(7a))_(g′)—(Z)_(k)—(W)_(h′)—(CR⁸R⁹)_(g″)—(W)_(h″)—(CR^(8a)R^(9a))_(g″′)—(W)_(h″′)—(CR^(8b)R^(9b))_(g″″)—; W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, SO₂NH, (OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), (CH₂CH₂CH₂O)_(t), and (aa)_(t′); aa is independently at each occurrence an amino acid; z is selected from the group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R^(8b), R⁹, R^(9a) and R^(9b) are independently selected at each occurrence from the group: H, ═O, COOH, SO₃H, PO₃H, C₁-C₅ alkyl substituted with 0-3 R¹⁰, aryl substituted with 0-3 R¹⁰, benzyl substituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to C_(h); R¹⁰ is independently selected at each occurrence from the group: a bond to C_(h), COOR¹¹, C(═O)NHR¹¹, NHC(═O)R¹¹, OH, NHR¹¹, SO₃H, PO₃H, —OPO₃H₂, —OSO₃H, aryl substituted with 0-3 R¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1 R¹², and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹¹; R¹¹ is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R¹², aryl substituted with 0-1 R¹², a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycol substituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹², cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1 R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substituted with 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C_(h); R¹² is a bond to C_(h); k is selected from 0, 1, and 2; h is selected from 0, 1, and 2; h′ is selected from 0, 1, 2, 3, 4, and 5; h″ is selected from 0, 1, 2, 3, 4, and 5; h″′ is selected from 0, 1, 2, 3, 4, and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; C_(h) is a metal bonding unit having a formula:

 wherein: A¹, A², A³, and A⁴ are NR¹³R¹⁴ wherein R¹³ and R¹⁴ are each an electron; E (between A¹ and A², A² and A³, A³ and A⁴, and A⁴ and A¹) is CH₂CH₂; A⁵, A⁶, and A⁷ are OH; A⁸ is NR¹³R¹⁴ wherein R¹³ is H and R¹⁴ is a bond to L_(n); and E (between A¹ and A⁵, A² and A⁶, A³ and A⁷, and A⁴ and A⁸) is CH₂C (═O).
 36. A compound according to claim 35, wherein: Q is a compound of Formula Ia:

 or pharmaceutically acceptable salt forms thereof, wherein: d is selected from 1, 2, 3, 4, and 5; W is independently selected at each occurrence from the group: O, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, (OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), and (CH₂CH₂CH₂O)_(t); Z is selected from the group: aryl substituted with 0-1 R¹⁰, C₃₋₁₀ cycloalkyl substituted with 0-1 R¹⁰, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R^(8b), R⁹, R^(9a) and R^(9b) are independently selected at each occurrence from the group: H, ═O, COOH, SO₃H, C₁-C₅ alkyl substituted with 0-1 R¹⁰, aryl substituted with 0-1 R¹⁰, benzyl substituted with 0-1 R¹⁰, and C₁-C₅ alkoxy substituted with 0-1 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to C_(h); R¹⁰ is independently selected at each occurrence from the group: a bond to C_(h), COOR¹¹, C(═O)NHR¹¹, NHC(═O)R¹¹, OH, NHR¹¹, SO₃H, PO₃H, —OPO₃H₂, —OSO₃H, aryl substituted with 0-3 R¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1 R¹², and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹¹; R¹¹ is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R¹², aryl substituted with 0-1 R¹², a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycol substituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹², cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1 R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substituted with 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C_(h); k is 0 or 1; s is selected from 0, 1, 2, 3, 4, and 5; s′ is selected from 0, 1, 2, 3, 4, and 5; s″ is selected from 0, 1, 2, 3, 4, and 5; and t is selected from 0, 1, 2, 3, 4, and
 5. 37. A compound according to claim 35, wherein: Q is a compound of Formula IIa or IIb:

 or pharmaceutically acceptable salt forms thereof wherein: W^(d) is —C(═O)—N(R^(13d))—; and R^(20d) is H or CH₃.
 38. A compound according to claim 35, wherein: Q is a compound of Formula IIa or IIb:

 or pharmaceutically acceptable salt forms thereof wherein: R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), halogen, CO₂R^(17d), CONR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d); R^(11d) is selected from: H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)R^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d); W^(d) is —C(═O)—N(R^(13d))—; R^(20d) is H or CH₃; and d is 1, 2, 3, 4, or
 5. 39. A compound according to claim 35, wherein the compound is selected from the group: 3-((1-(3-(imidazole-2-ylamino)propyl)(1H-indazol-5yl))carbonylamino)-2-(((4-(4-(((3-(2-(3-(2-(1,4,7,10-tertraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic acid; 2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-[2-(6-aminohexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonyl-amino)propanoic acid]; DOTA/N,N′-Bis(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)-2-(amino)pentane-1,5-diamide conjugate; DOTA/2-amino-4-(N-(3-(2-(2-(3-(((4-(4-(((1-carboxy-2-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)ethyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)butanoic acid salt; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-3-(4-(phosphonooxy)phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(III-indazol-5-yl)carbonylamino)propionic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-3-(4-(sulfooxy)phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl)carbonylamino)propionic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(ethyl-3,6-O-disulfo-β-D-galactopyranosyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(6-deoxy-β-cyclodextryl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(ω-methoxypolyethylene(5,000)glycoxyethyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate; 2-(((4-(3-(N-(3-(2-(2(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-aminohexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid salt; and DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino6-(2-bis(phosphonomethyl)amino)acetylamino)hexanolylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propionic acid conjugate; or a pharmaceutically acceptable salt form thereof.
 40. A kit comprising a compound of claim 35, or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier.
 41. A kit according to claim 39, wherein the kit further comprises one or more ancillary ligands and a reducing agent.
 42. A kit according to claim 41, wherein the ancillary ligands are tricine and TPPTS.
 43. A kit according to claim 42, wherein the reducing agent is tin(II).
 44. A diagnostic or therapeutic metallopharmaceutical composition, comprising: a compound according to claim 35 and a metal selected from the group consisting of ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, ⁶⁸Ga, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹Pm, ⁹⁰Y, ²¹²Bi, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu, Gd(III), Dy(III), Fe(III), Mn(II), Sm, Ho, Lu, Pm, Y, Bi, Gd, La, Au, Yb, Dy and Cu.
 45. A composition according to claim 44, wherein the metallopharmaceutical is a diagnostic radiopharmaceutical, and the metal is a radioisotope selected from the group: ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, and ⁶⁸Ga.
 46. A composition according to claim 45, wherein the radioisotope is ¹¹¹In.
 47. A composition according to claim 44, wherein the metallopharmaceutical is a therapeutic radiopharmaceutical, the metal is a radioisotope selected from the group: ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹Pm, ⁹⁰Y, ²¹²Bi, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, ¹⁶⁶Dy, and ⁶⁷Cu.
 48. A composition according to claim 47, wherein the radioisotope is ⁹⁰Y.
 49. A composition according to claim 44, wherein the metallopharmaceutical is a MRI contrast agent, the metal is a paramagnetic metal ion selected from the group: Gd(III), Dy(III), Fe(III), and Mn(II).
 50. A composition according to claim 49, wherein the metal ion is Gd(III).
 51. A composition according to claim 44, wherein the metallopharmaceutical is a X-ray contrast agent, the metal is selected from the group: Sm, Ho, Lu, Pm, Y, Bi, Gd, La, Au, Yb, Dy and Cu.
 52. A method of treating rheumatoid arthritis in a patient comprising: administering to said patient, by injection or infusion, a therapeutic effective amount of a radiopharmaceutical of claim
 44. 53. A method of treating cancer in a patient comprising: administering to said patient, by injection or radiopharmaceutical of claim
 47. 54. A method of imaging formation of new blood vessels in a patient comprising: (1) administering to said patient, by injection or infusion, a diagnostic effective amount of composition of claim 45; and (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.
 55. A method of imaging formation of new blood vessels in a patient comprising: (1) administering to said patient, by injection or infusion, a diagnostic effective amount of composition of claim 49; and (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.
 56. A method of imaging formation of new blood vessels in a patient comprising: (1) administering to said patient, by injection or infusion, a diagnostic effective amount of composition of claim 51; and (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.
 57. A method of imaging cancer in a patient comprising: (1) administering to said patient, by injection or infusion, a diagnostic effective amount of a radiopharmaceutical of claim 45 to a patient by injection or infusion; (2) imaging the patient using planar or SPECT gamma scintigraphy, or positron emission tomography.
 58. A method of imaging cancer in a patient comprising: (1) administering to said patient an effective amount of a MRI contrast agent of claim 49; and (2) imaging the patient using magnetic resonance imaging.
 59. A method of imaging cancer in a patient comprising: (1) administering an effective amount of a X-ray contrast agent of claim 51; and (2) imaging the patient using X-ray computed tomography.
 60. A therapeutic radiopharmaceutical composition, comprising: (a) a therapeutic radiopharmaceutical of claim 47; and, (b) a parenterally acceptable carrier.
 61. A composition, comprising: (a) a diagnostic or therapeutic metallopharmaceutical according to claim 44; and, (b) a parenterally acceptable carrier.
 62. A method of targeting a chelated metal to a receptor selected from the group consisting of α_(v)β₃ and α_(v)β₅, comprising chelating the metal with a compound of claim 35, and administering the chelated metal to a patient, wherein the metal is selected from the group consisting of ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, ⁶⁸Ga, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹Pm, ⁹⁰Y, ²¹²Bi, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu, Gd(III), Dy(III), Fe(III), Mn(II), Sm, Ho, Lu, Pm, Y, Bi, Gd, La, Au, Yb, Dy and Cu.
 63. A compound comprising: a first component comprising an indazole nonpeptide which binds to a receptor that is selected from the group consisting of EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Ax1, α_(v)β₃, α_(v)β₅, α₅β₁, α₄β₁, α₁β₁, and α₂β₂; and a second component comprising a chelator bound to said indazole nonpeptide; wherein said first and second component are bound through 0-1 linking groups.
 64. A compound according to claim 63, wherein the indazole nonpeptide of Formula Ia:

or pharmaceutically acceptable salt forms thereof, wherein: X^(1d), X^(2d), X^(3d), and X^(4d) are independently selected from nitrogen or carbon provided that at least two of X^(1d), X^(2d), X^(3d) and X^(4d) are carbon; R^(1d) is selected from:

A^(d) and B^(d) are independently —CH₂—, —O—, —N(R^(2d))—, or —C(═O)—; A^(1d) and B^(1d) are independently —CH₂— or —N(R^(3d))—; D^(d) is —N(R^(2d))—, —O—, —S—, —C(═O)— or —SO₂—; E^(d—F) ^(d) is —C(R^(4d))═C(R^(5d))—, —N═C(R^(4d))—, —C(R^(4d))═N—, or —C(R^(4d))₂C(R^(5d))₂—; J^(d), K^(d), L^(d) and M^(d) are independently selected from —C(R^(4d))—, —C(R^(5d))— or —N—, provided that at least one of J^(d), K^(d), L^(d) and M^(d) is not —N—; R²d is selected from: H, C₁-C₆ alkyl, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl; (C₁-C₆ alkyl)aminocarbonyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, heteroaryl(C₁-C₆ alkyl)carbonyl, heteroarylcarbonyl, aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl-, arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl, aryloxycarbonyl, or aryl(C₁-C₆ alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro; R^(3d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₁-C₆ alkyl)-; R^(4d) and R^(5d) are independently selected from: H, C₁-C₄ alkoxy, NR^(2d)R^(3d), halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl, or alternatively, when substituents on adjacent atoms, R^(4d) and R^(5d) can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃, or NO₂; U^(d) is selected from: —(CH₂)_(n) ^(d)—, —(CH₂)_(n) ^(d)(CR^(7d)═CR^(8d))(CH₂)_(m) ^(d)—, —(CH₂)_(n) ^(d)(C≡C)(CH₂)_(m) ^(d)—, —(CH₂)_(t) ^(d)Q(CH₂)_(m) ^(d)—, —(CH₂)_(n) ^(d)O(CH₂)_(m) ^(d)—, —(CH₂)_(n) ^(d)N(R^(6d))(CH₂)_(m) ^(d)—, —(CH₂)_(n) ^(d)C(═O)(CH₂)_(m) ^(d)—, —(CH₂)_(n) ^(d)(C═O)N(R^(6d))(CH₂)_(m) ^(d)— —(CH₂)_(n) ^(d)N(R^(6d))(C═O)(CH₂)_(m) ^(d)—, or —(CH₂)_(n) ^(d)S(O)_(p) ^(d)(CH₂)_(m) ^(d)—; wherein one or more of the methylene groups in U^(d) is optionally substituted with R^(7d); Q^(d) is selected from 1,2-cycloalkylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 2,4-pyridinylene, or 3,4-pyridazinylene; R^(6d) is selected from: H, C₁-C₄ alkyl, or benzyl; R^(7d) and R^(8d) are independently selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₀-C₆ alkyl)-; R^(10d) is selected from: H, C₁-C₄ alkoxy substituted with 0-1 R^(21d), N(R^(6d))₂, halogen, NO₂, CN, CF₃, CO₂R^(17d), C(═O)R^(17d), CONR^(17d)R^(20d), SO₂R^(17d), —SO₂NR^(17d)R^(20d), C₁-C₆ alkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₆ alkenyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₃-C₇ cycloalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), C₄-C₁₁ cycloalkylalkyl substituted with 0-1 R^(15d) or 0-1 R^(21d), aryl substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d), or aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(15d) or 0-2 R^(11d) or 0-1 R^(21d); R^(11d) is selected from H, halogen, CF₃, CN, NO₂, hydroxy, NR^(2d)R^(3d), C₁-C₄ alkyl substituted with 0-1 R^(21d), C₁-C₄ alkoxy substituted with 0-1 R^(21d), aryl substituted with 0-1 R^(21d), aryl(C₁-C₆ alkyl)-substituted with 0-1 R^(21d), (C₁-C₄ alkoxy)carbonyl substituted with 0-1 R^(21d), (C₁-C₄ alkyl)carbonyl substituted with 0-1 R^(21d), C₁-C₄ alkylsulfonyl substituted with 0-1 R^(21d), or C₁-C₄ alkylaminosulfonyl substituted with 0-1 R^(21d); W^(d) is selected from: —(C(R^(12d))₂)_(q) ^(d)C(═O)N(R^(13d))—, or —C(═O)—N(R^(13d))—(C(R^(12d))₂)_(q) ^(d)—; X^(d) is —C(R^(12d))(R^(14d))—C(R^(12d))(R^(15d))—; or alternatively, W^(d) and X^(d) can be taken together to be

R^(12d) is selected from H, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₄-C₁₀ cycloalkylalkyl, (C₁-C₄ alkyl)carbonyl, aryl, or aryl(C₁-C₆ alkyl)-; R^(13d) is selected from H, C₁-C₆ alkyl, C₃-C₇ cycloalkylmethyl, or aryl(C₁-C₆ alkyl)-; R^(14d) is selected from: H, C₁-C₆ alkylthio(C₁-C₆ alkyl)-, aryl(C₁-C₁₀ alkylthioalkyl)-, aryl(C₁-C₁₀ alkoxyalkyl)-, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₆ hydroxyalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, heteroaryl(C₁-C₆ alkyl)-, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), or CONR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0-1 R^(16d) or 0-2 R^(11d); R^(15d) is selected from: H, R^(16d), C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ alkylaminoalkyl, C₁-C₁₀ dialkylaminoalkyl, (C₁-C₁₀ alkyl)carbonyl, aryl(C₀-C₆ alkyl)carbonyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl(C₁-C₆ alkyl)-, heteroaryl(C₁-C₆ alkyl)-, aryl, heteroaryl, CO₂R^(17d), C(═O)R^(17d), CONR^(17d)R^(20d), SO₂R^(17d), or SO₂NR^(17d)R^(20d), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0-2 R^(11d); Y^(d) is selected from: —COR^(19d), —SO₃H, —PO₃H, tetrazolyl, —CONHNHSO₂CF₃, —CONHSO₂R^(17d), —CONHSO₂NHR^(17d), —NHCOCF₃, —NHCONHSO₂R^(17d), —NHSO₂R^(17d), —OPO₃H₂, —OSO₃H, —PO₃H₂, —SO₃H, —SO₂NHCOR^(17d), —SO₂NHCO₂R^(17d),

R^(16d) is selected from: —N(R^(20d))—C(═O)—O—R^(17d), —N(R^(20d))—C(═O)—R^(17d), —N(R^(20d))—C(═O)—NH—R^(17d), —N(R^(20d))SO₂—R^(17d), or —N(R^(20d))SO₂—NR^(20d)R^(17d); R^(17d) is selected from: C₁-C₁₀ alkyl optionally substituted with a bond to the linking group, C₃-C₁₁ cycloalkyl optionally substituted with a bond to the linking group, aryl(C₁-C₆ alkyl)-optionally substituted with a bond to the linking group, (C₁-C₆ alkyl)aryl optionally substituted with a bond to the linking group, heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to the linking group, (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to the linking group, biaryl(C₁-C₆ alkyl)-optionally substituted with a bond to the linking group, heteroaryl optionally substituted with a bond to the linking group, aryl optionally substituted with a bond to the linking group, or a bond to the linking group, wherein said aryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, heteroaryl, halo, cyano, amino, CF₃, and NO₂; R^(18d) is selected from: H, —C(═O)—O—R^(17d), —C(═O)—R^(17d), —C(═O)—NH—R^(17d), —SO₂—R^(17d), or —SO₂—NR^(20d)R^(17d); R^(19d) is selected from: hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy, aryloxy, aryl(C₁-C₆ alkoxy), C₃-C₁₀ alkylcarbonyloxyalkyloxy, C₃-C₁₀ alkoxycarbonyloxyalkyloxy, C₂-C₁₀ alkoxycarbonylalkyloxy, C₅-C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅-C₁₀ cycloalkoxycarbonylalkyloxy, C₇-C₁₁ aryloxycarbonylalkyloxy, C₈-C₁₂ aryloxycarbonyloxyalkyloxy, C₈-C₁₂ arylcarbonyloxyalkyloxy, C₅-C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅-C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀-C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R^(11d))(R^(12d))N—(C₁-C₁₀ alkoxy); R^(20d) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₁ cycloalkylalkyl, aryl, aryl(C₁-C₆ alkyl)-, or heteroaryl(C₁-C₆ alkyl)-; R²¹d is selected from: COOH or N(R^(6d))₂; m^(d) is 0-4; n^(d) is 0-4; t^(d) is 0-4; p^(d) is 0-2; q^(d) is 0-2; and r^(d) is 0-2; and with the following provisos: (1)_(t) ^(d), n^(d), m^(d) and q^(d) are chosen such that the number of atoms connecting R^(1d) and Y^(d) is in the range of 10-14; and (2)_(n) ^(d) and m^(d) are chosen such that the value of n^(d) plus m^(d) is greater than one unless U^(d) is —(CH₂)_(t) ^(d)Q^(d) (CH₂)_(m) ^(d)—.
 65. A compound according to claim 63, wherein the linking group is of the formula: —(CR⁶R⁷)_(g)—(W)_(h)—(CR^(6a)R^(7a))_(g′)(Z)_(k)—(W)_(h′)—(CR⁸R⁹)_(g″)—(W)_(h″)—(CR^(8a)R^(9a))_(g″′)—(W)_(″′)—(CR^(8b)R^(9b))_(g″″)—; W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, SO₂NH, (OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″), (CH₂CH₂CH₂O)_(t), and (aa)_(t′); aa is independently at each occurrence an amino acid; Z is selected from the group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), R⁸, R^(8a), R^(8b), R⁹, R^(9a) and R^(9b) are independently selected at each occurrence from the group: H, ═O, COOH, SO₃H, PO₃H, C₁-C₅ alkyl substituted with 0-3 R¹⁰, aryl substituted with 0-3 R¹⁰, benzyl substituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to the chelator; R¹⁰ is independently selected at each occurrence from the group: a bond to the chelator, COOR¹¹, C(═O)NHR¹¹, NHC(═O)R¹¹, OH, NHR¹¹, SO₃H, PO₃H, —OPO₃H₂, —OSO₃H, aryl substituted with 0-3 R¹¹, C₁₋₅ alkyl substituted with 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1 R¹², and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹¹; R¹¹ is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R¹², aryl substituted with 0-1 R¹², a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R¹², C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycol substituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹², cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1 R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substituted with 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to the chelator; R¹² is a bond to the chelator; k is selected from 0, 1, and 2; h is selected from 0, 1, and 2; h′ is selected from 0, 1, 2, 3, 4, and 5; h″ is selected from 0, 1, 2, 3, 4, and 5; h″′ is selected from 0, 1, 2, 3, 4, and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g″″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and
 10. 66. A compound according to claim 63, wherein the chelator is a metal bonding unit having a formula selected from the group:

A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at each occurrence from the group: NR¹³, NR¹³R¹⁴, S, SH, S(Pg), O, OH, PR¹³, PR¹³R¹⁴, P(O)R¹⁵R¹⁶, and a bond to the linking group; E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷; R¹³ and R¹⁴ are each independently selected from the group: a bond to the linking group, hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₁₋₁₀ substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³ or R¹⁴ is an electron, then the other is also an electron; alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹); R¹⁵ and R¹⁶ are each independently selected from the group: a bond to the linking group, —OH, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R¹⁷; R¹⁷ is independently selected at each occurrence from the group: a bond to the linking group, ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸, —C(═O)R¹⁸, —C(═O)N(R¹⁸)₂, —CHO, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)OR^(18a), —OR¹⁸, —OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂, —NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —SR¹⁸, —S(═O)R^(18a), —SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, NO₂, —C(═O)NHOR¹⁸, —C(═O)NHNR¹⁸R^(18a), —OCH₂CO₂H, 2-(1-morpholino)ethoxy, C₁-C₅ alkyl, C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylmethyl, C₂-C₆ alkoxyalkyl, aryl substituted with 0-2 R¹⁸, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O; R¹⁸, R^(18a), and R¹⁹ are independently selected at each occurrence from the group: a bond to the linking group, H, C₁-C₆ alkyl, phenyl, benzyl, C₁-C₆ alkoxy, halide, nitro, cyano, and trifluoromethyl; Pg is a thiol protecting group; R²⁰ and R²¹ are independently selected from the group: H, C₁-C₁₀ alkyl, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, C₂-C₁₀ 1-alkene substituted with 0-3 R²³, C₂-C₁₀ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3 R²³, unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R²³, and unsaturated C₃₋₁₀ carbocycle substituted with 0-3 R²³; alternatively, R²⁰ and R²¹, taken together with the divalent carbon radical to which they are attached form:

R²² and R²³ are independently selected from the group: H, R²⁴, C₁-C₁₀ alkyl substituted with 0-3 R²⁴, C₂-C₁₀ alkenyl substituted with 0-3 R²⁴, C₂-C₁₀ alkynyl substituted with 0-3 R²⁴, aryl substituted with 0-3 R²⁴, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R²⁴, and C₃₋₁₀ carbocycle substituted with 0-3 R²⁴; alternatively, R²², R²³ taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O; a and b indicate the positions of optional double bonds and n is 0 or 1; R²⁴ is independently selected at each occurrence from the group: ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, —N(R²⁵)₃+, —CH₂OR²⁵, —OC(═O)R²⁵, —OC(═O)OR^(25a), —OR²⁵, —OC(═O)N(R²⁵)₂, —NR²⁶C(═O)R²⁵, —NR²⁶C(═O)OR^(25a), —NR²⁶C(═O)N(R²⁵)₂, —NR²⁶SO₂N(R²⁵)₂, —NR²⁶SO₂R^(25a), —SO₃H, —SO₂R^(25a), —SR²⁵, —S(═O)R^(25a), —SO₂N(R²⁵)₂, —N(R²⁵)₂, ═NOR²⁵, —C(═O)NHOR²⁵, —OCH₂CO₂H, and 2-(1-morpholino)ethoxy; and, R²⁵, R^(25a), and R²⁶ are each independently selected at each occurrence from the group: hydrogen and C₁-C₆ alkyl.
 67. A metallopharmaceutical, comprising a compound according to claim 63; and a metal selected from the group consisting of ¹¹¹In, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, ⁶⁸Ga, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹Pm, ⁹⁰Y, ²¹²Bi, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, 166Dy, ⁶⁷CU, Gd(III), Dy(III), Fe(III), Mn(II), Sm, Ho, Lu, Pm, Y, Bi, Gd, La, Au, Yb, Dy and Cu, wherein the metal is bound to the chelator.
 68. A method of imaging formation of new blood vessels in a patient comprising: (1) administering a MRI contrast agent of claim 23 to a patient by injection or infusion; and (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.
 69. A method of imaging formation of new blood vessels in a patient comprising: (1) administering a X-ray contrast agent of claim 26 to a patient by injection or infusion; and (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.
 70. A method of treating cancer in a patient comprising: (i) selecting a radioisotope from the group consisting of ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁴⁹Pm, ⁹⁰Y, ²¹²Bi, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, 166Dy, and ⁶⁷Cu; (ii) forming a complex of the radioisotope and a compound according to claim 35; and (iii) administering the complex to a patient. 